Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.Br[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[N:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:21]1[CH:22]=[C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:18](=[O:25])[N:19]([CH3:24])[N:20]=1
Reactant: Nc1ccc(C(=O)N2CCOCC2)cn1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 93 °C
Yield: 71.7 %

Procedure:
(6-Aminopyridin-3-yl)(morpholino)methanone (58 g, 280 mmol, Eq: 1.00), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (63.66 g, 285 mmol, Eq: 1.02) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (4.86 g, 8.4 mmol, Eq: 0.03) were dissolved in DMF (1.1 l) under heating. Cesium carbonate (274 g, 840 mmol, Eq: 3) was added. Finally Pd2 (dba)3 (3.84 g, 4.2 mmol, Eq: 0.015) was added under an argon atmosphere. The reaction mixture was heated to 93° C. (internal temperature) for 3 hr. The warm reaction mixture was poured into water/ice (10 l). A beige precipitate was collected by filtration and washed with water (2 l). The resulting solid was taken up in DCM (51) and filtered. The filtrate was concentrated in vacuo to give a solid, which was triturated with isopropanol (700 ml), filtered and dried under vacuum to afford the desired product (70.24 g) as a beige solid. (M+H)+=350 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.56-3.79 (m, 8 H) 3.83 (s, 3 H) 6.96 (d, J=8.31 Hz, 1 H) 7.77 (dd, J=8.31, 2.27 Hz, 1 H) 8.34-8.42 (m, 2 H) 8.47 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[C:13]([NH:17][C:18]1[O:19][C:20]([C:27](Cl)=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[CH3:14][C:13]([NH:17][C:18]1[O:19][C:20]([C:27]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:28])=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)Cl)o1
Reactant: CC(O)CN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(O)CNC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Yield: 46.1 %

Procedure:
By the procedure of Example 38, a stirred mixture of 70 ml methylene chloride, 1.80 g (24 mmol) of 1-amino-2-propanol, 2.68 g (13.2 mmol) of triethylamine, and 6.50 g (24 mmol) of 2-(tert-butylamino)-4-trifluoromethyl-5-oxazolecarbonyl chloride was reacted for 16 hours at ambient temperature. The product was separated and then recrystallized to yield 3.42 g of a white solid product (m.p.=105°-107° C.) identified in Table I.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH3:26])=[CH:4]/[C@@H:5]1[C@:22]2([CH3:23])[C@@:8]([OH:25])([C@H:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C@@H:12]([CH2:13][C@@H:14]([OH:24])[CH2:15][CH2:16]2)[CH2:11][CH2:10]3)[CH2:7][CH2:6]1>C(Cl)(Cl)Cl.O=[Mn]=O>[OH:24][C@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:22]2([CH3:23])[C@:8]3([OH:25])[CH2:7][CH2:6][C@@H:5]2/[CH:4]=[C:3](\[CH3:26])/[CH:2]=[O:1])[CH2:13]1
Reactant: C/C(=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)CO
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 8.40 g of (E)-21-hydroxymethyl-21-methyl-5β-pregn-20-ene-3β,14β-diol in 200 ml of chloroform, 84.0 g of MnO2 were added at room temperature. The mixture was stirred overnight and then filtered through Celite. The organic solution was evaporated to dryness to give 7.50 g of the title compound (II-a) as an off-white solid.
Reaction SMILES: [F:1][C:2]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])([F:19])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[C:11]([O:17][CH3:18])[CH:10]=1.N1CCCCC1.C(O)(=O)C.[C:38]([O:44][CH2:45][CH3:46])(=[O:43])[CH2:39][C:40]([CH3:42])=[O:41]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:20]([C:2]([F:19])([F:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[C:39](\[C:40](=[O:41])[CH3:42])/[C:38]([O:44][CH2:45][CH3:46])=[O:43])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:24][CH2:25][CH3:26])=[O:27])[CH3:23]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOc1ccc(C=O)c(OC)c1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: CCOC(=O)/C(=C/c1ccc(OCCOCCC(F)(F)P(=O)(OCC)OCC)cc1OC)C(C)=O
Temperature: 110 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of diethyl (1,1-difluoro-3-(2-(4-formyl-3-methoxyphenoxy)ethoxy)propyl)phosphonate (1 equiv.) in toluene (0.50 M) was added piperidine (0.10 equiv.), acetic acid (0.50 equiv.) and ethyl acetoacetate (1.2 equiv.). The reaction mixture was then heated to 110° C. for 18 h. At this point additional piperidine (0.10 equiv.), acetic acid (0.50 equiv.) and ethyl acetoacetate (0.50 equiv.) were added to the reaction mixture and heating at 110° C. was continued for 4 h. At this point the reaction mixture was allowed to cool to room temperature and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH™ system using a gradient of 0-5% MeOH/DCM to provide the title compound (78%) as a solid.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:4]2[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: COc1ccccc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(C(=O)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Anisole (13.9 g, 0.13 mol) is added to a stirred solution of 4-chlorophenylacetic acid (20.0 g, 0.12 mol) in trifluoroacetic anhydride (16.5 ml, 0.12 mol). The mixture is stirred in room temperature for 24 h. Ice water is added and the crystallized product is collected on a sinter and washed with water. The product is recrystallized from ethanol. The yield is 20.4 g, 67%.
Reaction SMILES: [O:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:2]1=[O:3].[CH2:12]([NH:15][CH2:16][CH:17]=[CH2:18])[CH:13]=[CH2:14]>C1(C)C=CC=CC=1>[CH2:12]([N:15]([CH2:16][CH:17]=[CH2:18])[C:2](=[O:3])[CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[OH:1])[CH:13]=[CH2:14]
Reactant: C=CCNCC=C
Reactant: O=C1CCc2ccccc2O1
Solvent: Cc1ccccc1
Product: C=CCN(CC=C)C(=O)CCc1ccccc1O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
19.5 g of dihydrocoumarine was placed in a 250 ml round bottom flask with 20 ml of diallyl amine and 60 ml of toluene. The reaction mixture was stirred for 6 hrs at 50° C. The reaction mixture was then cooled, concentrated, and extracted with ethyl acetate and water. The organic phase was collected and concentrated to obtain dried solid. The obtained solid was recrystallized with ethyl acetate/n-hexane, filtered, washed with n-hexane, and vacuumed to dryness. 17.2 g of the product of formula (VIII) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH:11]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[C:16]([CH3:31])[CH:15]=2)[CH3:12])=[CH:9][CH:10]=1)=[O:5])C.[OH-].[Li+].Cl>C1COCC1>[CH3:20][C:18]1[CH:19]=[C:14]([O:13][CH:11]([C:8]2[S:7][C:6]([C:4]([OH:5])=[O:3])=[CH:10][CH:9]=2)[CH3:12])[CH:15]=[C:16]([CH3:31])[C:17]=1[C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1ccc(C(C)Oc2cc(C)c(-c3ccc(C(F)(F)F)cc3)c(C)c2)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(OC(C)c2ccc(C(=O)O)s2)cc(C)c1-c1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a mixture of (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid ethyl ester (0.636 g, 1.42 mmol) in THF (14 mL) is added lithium hydroxide (1N aqueous, 14 mL). The mixture is warmed to 70° C. and stirred overnight. The reaction mixture is acidified with 1N HCl (15 mL), extracted into ethyl acetate (3×25 mL), dried over MgSO4, and concentrated, to provide (±)-5-[1-(2,6-dimethyl-4′-trifluoromethyl-biphenyl-4-yloxy)-ethyl]-thiophene-2-carboxylic acid (0.552 g, 92%) as a white foam. MS (ES): 419.2 [M−H]−.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[C:12]([CH2:18][CH3:19])([CH3:17])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[C:12]([CH2:18][CH3:19])([CH3:17])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC1(C)CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C)CN(Cc2ccccc2)CCC1O
Reaction time: 2 h

Procedure:
Sodium borohydride (0.3 g, 9.0 mmole) was added to the stirred solution of the 1-benzyl-3-ethyl-3-methylpiperid-4-one (1.5 g, 6.5 mmole) in methanol (20 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 2 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate (2×50 ml). The extract was dried over sodium sulphate and concentrated to dryness to furnish 1-benzyl-3-ethyl-4-hydroxy-3-methylpiperidine product as oil, which was used as such in the next step. Yield 1.1 g (74%), C15H23NO, m/z 234 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[CH3:11][CH:12]([CH3:35])[CH:13]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=2)=[CH:24][N:25]=1)=[O:20])[C:14]([O:16][CH3:17])=[O:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[S:22][C:21]([C:19]([NH:18][CH:13]([CH:12]([CH3:35])[CH3:11])[C:14]([O:16][CH3:17])=[O:15])=[O:20])=[N:25][CH:24]=2)=[CH:27][CH:28]=1
Reactant: O=C=Nc1ccccc1Cl
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NC(=O)Nc3ccccc3Cl)cc2)s1)C(C)C
Yield: 87 %

Procedure:
The title compound was synthesized analogous to Example 9, using 1-chloro-2-isocyanatobenzene and intermediate 2. Yield: 87%; 1HNMR (DMSO-d6, 300 MHz): δ 9.67 (s, 1H), 8.74 (d, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.15 (dd, 1H), 7.75 (d, 2H), 7.6 (d, 2H), 7.49 (dd, 1H), 7.32 (m, 1H), 7.06 (m, 1H), 4.33, (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.95 (d, 6H); MS (ES+): m/z 487 (M+1).
Reaction SMILES: N[C:2]1[C:3]([O:23][CH3:24])=[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].Cl.N([O-])=O.[Na+].[I-:30].[K+]>>[Cl:8][C:7]1[CH:6]=[C:5]([F:9])[C:4]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:3]([O:23][CH3:24])[C:2]=1[I:30]
Reactant: COc1c(N)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Product: COc1c(I)c(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Temperature: 15 °C
Reaction time: 0.33 h
Yield: 57 %

Procedure:
A solution of 4.0 grams (0.011 mole) of 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione in 25 mL (0.300 mole) of concentrated hydrochloric acid was stirred and cooled in an ice bath. During a 15 minute period, 1.9 grams (0.013 mole) of sodium nitrite was added dropwise at a rate to maintain the reaction temperature at 15° C. Upon completion of addition, the mixture was stirred for 20 minutes and then poured into 15.0 grams (0.090 mole) of potassium iodide. The reaction mixture was stirred for 30 minutes and then filtered. The filter cake was thoroughly washed with distilled water and then taken up in 150 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a brown solid. The solid was subjected to column chromatography on silica gel. Elution was accomplished using 5:1 heptane and ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 3.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: FC1C=CC([S:8]([Cl:11])(=[O:10])=[O:9])=CC=1OC.N[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1>>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:16][C:17]=1[C:23]([F:26])([F:25])[F:24])#[N:20]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: COc1cc(S(=O)(=O)Cl)ccc1F
Product: N#Cc1ccc(S(=O)(=O)Cl)cc1C(F)(F)F

Procedure:
The titled compound is prepared analogously to 4-fluoro-3-methoxy-benzenesulfonyl chloride (Intermediate 102a) by replacing 4-fluoro-3-methoxyaniline with 4-amino-2-trifluoromethyl-benzonitrile.
Reaction SMILES: [C:1]1(=[CH:6][C:7](=[O:9])[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([CH2:15][C:16](=[O:18])[CH3:17])CCC[CH:11]=1.C(CC(=O)C)(=O)C>C1C=CC=CC=1.CCCCCCC.[Cl-].[Zn+2].[Cl-]>[C:7]([CH:6]1[C:1]2([CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:17][C:16](=[O:18])[CH:15]=[C:10]1[CH3:11])(=[O:9])[CH3:8]
Reactant: CC(=O)C=C1CCCC1
Reactant: CC(=O)CC1=CCCC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CC(=O)C1C(C)=CC(=O)CC12CCCC2
Yield: 2.1 %

Procedure:
In a Dean-Stark apparatus, a mixture of 1-cyclopentylidenepropan-2-one/1-cyclopentenylpropan-2-one (25:75, 600 g, 4.83 mol), acetylacetone (493 g, 4.83 mol), and zinc chloride (164.6 g, 1.21 mol) in benzene (500 ml) and heptane (500 ml) was heated at reflux for 2.5 d (44 ml water collected). The reaction mixture was poured into ice/water (1.5 l) and extracted with cyclohexane (0.6 l). The organic phase was washed with water (1 l), with a saturated aqueous solution of NaHCO3 (0.5 l), twice with a saturated aqueous solution of NaCl (1 l and 0.5 l), dried (100 g MgSO4), and concentrated (till 60° C./30 mbar). Vigreux-Distillation (0.08 mbar, bath temperature 180° C., head temp. 120-130° C.) of the crude product (615 g) followed by FC (2 kg SiO2, hexane/MTBE 2:1) gave 10-acetyl-9-methylspiro[4.5]dec-8-en-7-one (20.7 g, 2.1%). Boiling point: 150° C. (0.09 mbar).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([O:20][Si](C(C)(C)C)(C)C)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F.N1C=CC=CC=1>C1COCC1.CCOCC>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:14][C:13]1([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(O[Si](C)(C)C(C)(C)C)CC1NC(=O)OCc1ccccc1
Agent: F
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)C1(O)CC1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of ethyl 2-(benzyloxycarbonylamino)-1-(tert-butyldimethylsilyloxy)cyclopropanecarboxylate (1.45 g, 3.69 mmol) in THF (35 mL) under N2 was added HF•pyridine (1.0 mL, 38 mmol). The reaction mixture was stirred for 5 h. After this time, additional HF•pyridine (1.0 mL, 38 mmol) was added and stirring was continued for 19 h. The reaction mixture was then cooled to 0° C. and diluted with Et2O (150 mL). The mixture was then carefully quenched with saturated aqueous NaHCO3 until gas evolution ceased. At this time, the organic layer was separated and the remaining aqueous layer was extracted with Et2O (300 mL). The combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography eluting with 20%-50% EtOAc/hexanes afforded the title compound (0.960 g, 93%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.30 (m, 5H), 5.11-4.83 (m, 3H), 4.21 (q, J=7.2 Hz, 2H), 3.37-3.25 (m, 2H), 1.73-1.68 (m, 1H), 1.27 (t, J=7.2 Hz, 3H), 1.14-1.06 (m, 1H); ESI MS m/z 280 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Br)[CH:15]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)[CH:15]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2ccc([N+](=O)[O-])n2)c1
Temperature: 0 °C
Yield: 82.3 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 1.00 g, 8.84 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL) and a 60% dispersion of sodium hydride in mineral oil (423 mg, 10.61 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 25 min, the reaction was chilled to 0° C. and the 3-bromomethyl-benzoic acid methyl ester (2.11 g, 9.20 mmol) was added. The reaction continued to stir under nitrogen at 0° C. for 20 min. The reaction was diluted with ethyl acetate (200 mL), washed with water (2×50 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to give an orange oil. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 120 g; 10% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-(3-nitro-pyrazol-1-ylmethyl)-benzoic acid methyl ester (1.90 g, 82%) as a white waxy solid: H1-NMR (400 MHz, CDCl3) δ 3.93 (3H, s), 5.42 (2H, s), 6.91 (1H, d, J=2.0 Hz), 7.42-7.48 (3H, m), 7.97 (1H, s), 8.03-8.04 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].I[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.CN1CCOCC1.Cl>CC(O)C(O)C.Cl[Cu]>[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([NH:1][C:2]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:17]=1
Reactant: Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: Cc1ccc(I)cc1
Agent: Cl[Cu]
Agent: CC(O)C(C)O
Agent: Cl
Solvent: CN1CCOCC1
Product: Cc1ccc(Nc2cc(C(=O)O)ccc2C(=O)O)cc1
Temperature: 150 °C

Procedure:
To a mixture of 2-amino-terephthalic acid (2.5 g, 23.8 mmol) and 1-iodo-4-methyl-benzene (7.78 g, 35.7 mmol) in butane-2,3-diol (38 mL) was added Cu (24 mg, 0.016 mmol), CuCl (950 mg, 9.6 mmol), and n-methyl morpholine (6.5 mL) under argon. The mixture was heated at 150° C. for 18 h. The reaction mixture was cooled to room temperature and HCl (0.1 N, 100 mL) was added. The resulting yellow precipitate was collected by filtration and triturated in a mixture of Et2O and EtOAc (1:1, 50 mL) for 1 h. The yellow solid was filtered, washed with ether (25 mL), and dried in vacuo to give 2.4 of 138A. HPLC retention time=3.046 min., condition A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13](Cl)(=[O:17])/[CH:14]=[CH:15]/[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:17])/[CH:14]=[CH:15]/[CH3:16])[CH:9]=2)[CH:4]=1
Reactant: C/C=C/C(=O)Cl
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C/C=C/C(=O)c1ccc2cc(OC)ccc2c1
Yield: 69 %

Procedure:
2-methoxynaphthalene (158 mg), crotonoyl chloride (124 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (156 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Br.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: CN(C)C(=O)c1cc2cc(F)cc(N3CCNCC3)c2o1
Reactant: BrCCc1ccccn1
Agent: Br
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2cc(F)cc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
A reaction mixture of 5-fluoro-N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.10 g, 0.35 mmol), 2-(2-bromoethyl)pyridine:HBr (0.132 g, 0.49 mmol) and triethylamine (0.12 mL, 0.88 mmol) was heated at 80° C. over night. The product was purified by preparative HPLC to give the title compound. Yield: 0.091 g (65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].[CH2:27]([O:29][P:30]([C:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44]Br)=[CH:40][C:39]=1[Br:46])([F:37])[F:36])(=[O:34])[O:31][CH2:32][CH3:33])[CH3:28]>CN(C=O)C>[CH2:32]([O:31][P:30]([C:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[CH:40][C:39]=1[Br:46])([F:37])[F:36])(=[O:34])[O:29][CH2:27][CH3:28])[CH3:33]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(CBr)cc1Br
Reactant: Clc1ccc(Nc2nc(-c3ccccc3)cs2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CN(c2ccc(Cl)c(Cl)c2)c2nc(-c3ccccc3)cs2)cc1Br
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
To (3,4-Dichloro-phenyl)-(4-phenyl-thiazol-2-yl)-amine (0.34 g, 1.04 mmol) in DMF (5 mL) was added K2CO3 (0.23 g, 1.71 mmol). After 0.1 hour, [(2-Bromo-4-bromomethyl-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester (0.15 g, 0.34 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and H2O, after which the organic layer was dried over NaSO4 and concentrated in vacuo. The resulting material was purified via column chromatography (1/1 hexanes/ethyl acetate) to yield 0.176 g (76%) of a clear, colorless oil; 1H NMR (300 MHz, CDCl3) δ 7.84-7.22 (m, 11 H), 6.81 (s, 1 H), 5.23 (s, 2 H), 4.23 (m, 4 H), 1.31 (t, J=7.5 Hz, 6 H).
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:9]1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:29][C:30]1C(F)=[N:32][CH:33]=[CH:34][CH:35]=1>ClCCl.FC(F)(F)C(O)=O.CS(C)=O>[S:14]1[C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=[C:13]1[NH:12][C@H:10]1[CH2:9][C@H:8]([NH:7][C:6]2[C:30]([Br:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: Fc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
Tert-butyl(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (intermediate 10, 1.16 g, 3.63 mmol) was dissolved in a mixture of dichloromethane (50 mL) and trifluoroacetic acid (10 mL). The solution was stirred for 20 minutes then evaporated to dryness under reduced pressure and further dried under high vacuum at 60° C. The crude amine was treated with cesium carbonate (2.85 g, 8.75 mmol) and dissolved in dry dimethylsulfoxide (5 mL). 3-Bromo-2-fluoropyridine (0.400 ml, 3.89 mmol) was added in one portion and the reaction heated at 110° C. After 2½ hours, another portion of 3-bromo-2-fluoropyridine (0.100 mL) was added and the reaction heated for another 12 hours. Additional 3-bromo-2-fluoropyridine (0.100 mL) was added and the heating continued for another 2 hours. The reaction was cooled and partitioned between 20% saturated sodium bicarbonate (200 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired trans-N1-(benzo[d]thiazol-2-yl)-N3-(3-bromopyridin-2-yl)cyclobutane-1,3-diamine (0.869 g, 2.316 mmol, 63.8% yield) as a yellow oil that solidified on standing.