Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[C:5](I)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:3]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O>>[CH3:1][C:2]1([CH3:19])[C:6](=[O:7])[C:5]([C:21]2[O:20][CH:24]=[CH:23][CH:22]=2)=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:3]1
Reactant: OB(O)c1ccco1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(I)C1=O
Product: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccco2)C1=O
Yield: 22.2 %

Procedure:
250 mg of 2,2-dimethyl-4-iodo-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was 86 mg of furan-2-boronic acid by a procedure similar to the procedure in Example 2 to afford 47 mg of 2,2-dimethyl-4-(2-furanyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone as a solid. NMR: δ1.56 (s, 6H), 3.11 (s, 3H), 6.51 (m, 1H), 6.89 (d, J=3.6 Hz, 1H), 7.37 (d, J=3.6 Hz, 1H), 7.97 (m, 4H). IR (cm−1): 2989, 1703, 1409, 1317, 2989, 1703, 1409, 1317, 1148, 959, 771.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]1([N:8]([CH3:10])[CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[C:32]([CH3:34])[C:28]([C:29](Cl)=[O:30])=[C:27]([CH3:35])[CH:26]=1>C(Cl)Cl>[CH3:9][N:8]([CH3:10])[C:3]1([CH:2]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:1][C:29](=[O:30])[C:28]2[C:27]([CH3:35])=[CH:26][C:25]([F:24])=[CH:33][C:32]=2[CH3:34])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(C(N)c2ccccc2)CCCC1
Reactant: Cc1cc(F)cc(C)c1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(F)cc(C)c1C(=O)NC(c1ccccc1)C1(N(C)C)CCCC1
Yield: 100 %

Procedure:
To {1-[amino(phenyl)methyl]cyclopentyl}dimethylamine D3 enantiomer 2 (0.904 g; 4.147 mmol) in DCM (45 ml) under argon at room temperature was added triethylamine (0.573 ml; 4.15 mmol), followed by a solution of 4-fluoro-2,6-dimethylbenzoyl chloride (0.773 g: 4.144 mmol) in DCM (5 ml). After 16 h. the reaction was washed with water, dried with MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with an ethyl acetate-hexane 0 to 100% gradient to give the title compound (1.57 g; 100%). 1H NMR (CDCl3) δ: 0.85-1.00 (1H, m), 1.30-1.60 (3H, m), 1.60-1.75 (2H, m), 1.75-1.90 (2H, m), 2.22 (6H, s), 2.31 (6H, m), 5.18 (1H, d, J=6 Hz), 6.73 (2H, d, J=9.6 Hz overlaps 1H, br s), 7.20-7.35 (3H, m), 7.42 (2H, m). Mass Spectrum (Electrospray LC/MS): Found 369 (MH+). C23H29FN2O requires 368. Ret. time 1.99 min. The free base was dissolved in methanol. 1M HCl/diethylether was added to the stirred solution and stirring continued at room temperature for 5 minutes. The solution was then evaporated under reduced pressure, redissolved in DCM and evaporated at reduced pressure. The resulting foam was dried for 16 hours at reduced pressure. The hydrochloride salt was obtained as a white foam (1.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][Cl:12])=[C:4]([CH:3]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cc(Br)ccc1SCCCCl
Solvent: CO
Product: Nc1cc(Br)ccc1SCCCCl
Reaction time: 72 h
Yield: 64.2 %

Procedure:
4-Bromo-1-[(3-chloropropyl)sulfanyl]-2-nitrobenzene (1.97 g, 7.1 mmol) was dissolved in MeOH (25 mL). The reaction flask was evacuated with nitrogen, and Pd(OH)2 on carbon (400 mg) was added. The reaction flask was evacuated with nitrogen several time before being subjected to an atmosphere of H2 (50 psi). The flask was shaken on a parr apparatus for 72 hrs. The reaction was filtered over a bed of celite and the residue was washed with MeOH (5 mL). The supernant was concentrated, and the crude, balck residue was purified by column chromatography (50-20% hexanes-CH2Cl2), to afford 5-bromo-2-[(3-chloropropyl)sulfanyl]aniline (1.28 g, 73%) as a clear oil. 1H NMR (CDCl3, 300 Mhz) δ7.20 (d, 1H, 8.0 Hz), 6.88 (d, 1H, 2.0 Hz), 6.79 (dd, 1H, 2.0 Hz, 8.0 Hz), 4.41 (s, 2H), 3.64 (t, 2H, 6.6 Hz), 2.86 (t, 2H, 7.0 Hz), 1.94-1.99 (m, 2H) ppm.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][N:4]=1.Br[CH2:15][CH2:16][O:17][CH3:18].CC([O-])(C)C.[K+]>O1CCOCC1>[CH3:18][O:17][CH2:16][CH2:15][CH:9]([C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][CH:5]=1)[C:10]#[N:11]
Reactant: COCCBr
Reactant: N#CCc1cnc(C(F)(F)F)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCCC(C#N)c1cnc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of 2-(2-(trifluoromethyl)pyrimidin-5-yl)acetonitrile (500 mg, 2.67 mmol) and 1-bromo-2-methoxyethane (419 mg, 2.81 mmol) in 1,4-dioxane (5 mL) was degassed and added t-BuOK (2.81 mL, 2.81 mmol, 1M in THF) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched by sat.NH4Cl and extracted with EtOAc (3×10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude product was purified by flash column chromatography (EtOAc: petroleum ether=1:10) to give 4-methoxy-2-(2-(trifluoromethyl)pyrimidin-5-yl)butanenitrile (100 mg, yield: 15%, 85% purity in LCMS, [M+H]=246).
Reaction SMILES: C([O:5][C:6](=[O:58])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:57])[CH2:15][CH2:16][S:17][CH2:18][CH:19]([O:39][C:40](=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[C:40]([O:39][CH:19]([CH2:20][O:21][C:22](=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][S:17][CH2:16][CH2:15][C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:58])=[O:5])=[CH:8][CH:9]=1)=[O:57])(=[O:56])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid t-butyl ester as obtained in Example 45 (1.05 g) in chloroform (5 ml)-trifiuoroacetic acid (6 ml) was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was crystallized from methanol-water to yield 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid (992 mg, yield 100%) as a colorless crystal. A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaheptanoylamino]benzoic acid as obtained above (200 mg), 7-t-butyl ester-glutamyl-glutamic acid di-t-butyl ester as obtained in Reference Example 26 (126 mg), DEPC (63 mg) and triethylamine (78 mg) in dimethylformarnide (6 ml) was stirred at room temperature for 30 minutes. The solvent was concentrated; the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:chloroform=2:1) to yield the title compound (210 mg, yield 68%) as a colorless amorphous substance.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH2:27])[C:22](=[O:25])[CH2:23]Br>>[CH3:20][N:21]([C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH2:27])[C:22](=[O:25])[CH2:23][N:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16]1
Reactant: C=C(c1ccccc1)N(C)C(=O)CBr
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: C=C(c1ccccc1)N(C)C(=O)CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (25) synthesized in Reference Example 25 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32].[CH3:41][C:42]1[S:43][CH:44]=[C:45]([CH:47]=O)[N:46]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Br:32])=[CH:47]/[C:45]1[N:46]=[C:42]([CH3:41])[S:43][CH:44]=1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br)P(=O)(OC)OC
Reactant: Cc1nc(C=O)cs1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1csc(C)n1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Br
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 91.8 %

Procedure:
1,1,3,3-Tetramethylguanidine (50 μL, 0.397 mmol) was added to a solution of rac.-N-[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 130; 100 mg, 0.189 mmol) in tetrahydrofuran (2 mL) at −40° C. The solution was stirred at −40° C. for 5 min and then 2-methylthiazole-4-carboxaldehyde (Example 41; 48 mg, 0.378 mmol) was added. The solution was stirred at −40° C. for 1 h and then allowed to stir at room temperature for 4 h. The solution was quenched with pH 6 phosphate buffer, diluted with ethyl acetate (15 mL) and the separated organic layer was washed with pH 6 phosphate buffer (10 mL) and brine (10 mL). The organic phase was dried (MgSO4), filtered, evaporated and triturated with diethyl ether to give (Z)-2-[[2-bromo-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-methylthiazol-4-yl)propenoic acid methyl ester (92 mg, 49% yield) as a brown solid.
Reaction SMILES: [N+:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)([O-])=O>[Pd]>[NH2:1][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=[N+]([O-])N1CCc2ccccc21
Agent: [Pd]
Product: NN1CCc2ccccc21

Procedure:
Substituted indolines are prepared such as by the procedures described in Scheme 20. Substituted aminoindolines 59 are prepared from the nitroindoline 57 and a ketone in the presence of NaHB(OAc)3 to form the 1-substituted indoline 58. The nitroindoline 58 is hydrogenated, such as with H2 in the presence of a catalyst, such as Pd/C, to yield the amino-indoline 59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[S:10]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21]([NH2:24])(=[O:23])=[O:22])(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(F)cc1NS(=O)(=O)/C=C/c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(F)cc1NS(=O)(=O)CCc1ccc(Cl)cc1
Yield: 49.3 %

Procedure:
2-[[(E)-2-(4-Chlorophenyl)ethenyl]sulfonylamino]-4-fluoro-benzenesulfonamide (120 mg, 0.31 mmol) was dissolved in ethyl acetate (5 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C). The product obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (60 mg, 49%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]([NH:21]C(=O)OC(C)(C)C)[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:29][CH2:30][N:31]3[C@H:36]4[CH2:37][CH2:38][C@@H:32]3[CH2:33][CH:34]([N:39]3[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=5[N:41]=[C:40]3[CH3:48])[CH2:35]4)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[C@@H:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1
Agent: Cl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)[C@@H](N)C(C)(C)C)CC1
Yield: 99.2 %

Procedure:
2,2,2-trifluoro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}carbamate (0.591 g, 0.90 mmol) with HCl as outlined in the procedure for Example 890 to form (2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.500 g, 99%). 2S)-1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-3,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), trifluoroaceticanhydirde (0.019 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2,2,2-trifluoro-N-{(1S)-1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-2,2-dimethylpropyl}acetamide (0.033 g, 56%) as an oil. ES-LCMS m/z 656 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([C:9]3[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=3)[CH2:7][S:8][C@H:3]12.[C:35]1([CH2:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)CC)C>ClCCl>[C:35]1([CH2:41][C:42]([NH:1][CH:2]2[C:33](=[O:34])[N:4]3[C:5]([C:17]([O:19][CH:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[C:6]([C:9]4[S:10][C:11]([N:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1nnc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Yield: 83.8 %

Procedure:
To a solution of 0.491 g of benzhydryl 7-amino-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate (obtained in Example 26) in 16 ml of dichloromethane is dropwise added 0.160 g of phenylacetylchloride and 0.10 g of triethylamine with stirring under ice-cooling, and stirring and cooling are maintained for 30 minutes. The reaction mixture is washed with water, dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residue is chromatographed on a column of silica gel [eluted with benzene-ethyl acetate(1:3)] to give 0.51 g of benzhydryl 7-phenylacetamido-3-(5-dimethylamino-1,3,4-thiadiazol-2-yl)-3-cephem-4-carboxylate.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)=[CH:26][CH:25]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1
Product: O=C1CCC(c2ccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH3:22]>CC(C)=O>[CH2:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)[CH3:22]
Reactant: Ic1ccc(N2CCNCC2)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCN1CCN(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 84.9 %

Procedure:
To a stirred mixture of 1-(4-iodophenyl)piperazine (5.76 g, 20 mmol) and K2CO3 (5.44 g, 40 mmol) in acetone (200 mL) was added iodoethane (2.58 mL, 32 mmol) dropwise over 1 min. After addition, the resulting mixture was stirred at rt for 21 h. The resulting precipitate was filtered off and rinsed with EtOAc (2×60 mL). The filtrate was concentrated to dryness to give a whiteish yellow solid. Trituration with MeOH (10 mL) and H2O (250 mL), followed by suction filtration (rinsed with H2O) gave the title compound as a yellow solid (5.37 g, 85%) after drying. 1H NMR (400 MHz, DMSO-d6) δ 7.46 (d, J=7.6 Hz, 2H), 6.76 (d, J=8.0 Hz, 2H), 3.13-3.07 (m, 4H), 2.48-2.43 (m, 4H), 2.34 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); MS ESI 317.0 [M+H]+, calcd. for [C12H171N2+H]+ 317.0.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[N+:29]([O-:31])=[O:30]>>[F:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([N+:29]([O-:31])=[O:30])[CH:16]=1
Reactant: Fc1cccc(C(F)(F)F)c1Br
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Using the procedure for step A in Example 4, the title compound was prepared from 1-bromo-2-fluoro-6-trifluoromethylbenzene (0.850 mL, 6.09 mmol) and 4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 2.09 g, 7.92 mmol) in 89% yield (1.62 g). 1H-NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.53-7.61 (m, 1H), 7.43-7.53 (m, 1H), 7.35 (t, J=8.5 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.47 (br. s., 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1>>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:14])[N:16]([C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)[CH3:15])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(N=C=O)cc1
Reactant: CCOC(=O)CCc1ccc(-c2cccc(NC)c2)cc1
Product: CCCCOc1ccc(NC(=O)N(C)c2cccc(-c3ccc(CCC(=O)OCC)cc3)c2)cc1
Yield: 97.4 %

Procedure:
In a manner similar to that of Example (5a), by reaction of 574 μl (3.17 mmol, 3 eq) of 4-butoxyphenyl isocyanate and 300 mg (1.06 mmol, 1 eq) of ethyl 3-(3′-methylaminobiphenyl-4-yl)propanoate at 100° C. by microwave for 15 minutes, 490 mg of ethyl 3-{3′-[3-(4-butoxyphenyl)-1-methylureido]biphenyl-4-yl}propanoate are obtained in the form of a white solid. Yield=97%
Reaction SMILES: [Br:1][C:2]1[C:3]2[O:22][CH2:21][CH2:20][C:19]([OH:23])=[C:18]([C:24]#[N:25])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2.[CH:26]([C:28]([CH3:30])=[O:29])=[CH2:27]>COCCOC>[Br:1][C:2]1[C:3]2[O:22][CH2:21][CH2:20][C:19](=[O:23])[C:18]([CH2:27][CH2:26][C:28](=[O:29])[CH3:30])([C:24]#[N:25])[C:4]=2[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:8]=[CH:7]2
Reactant: C=CC(C)=O
Reactant: N#CC1=C(O)CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Solvent: COCCOC
Product: CC(=O)CCC1(C#N)C(=O)CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reaction time: 47 h

Procedure:
TEA (0.300 mL, 2.152 mmol) was added to a slurry of 10-bromo-1-(4-fluorophenyl)-6-hydroxy-7,8-dihydro-1H-oxepino[3,2-f]indazole-5-carbonitrile (102, R1=4-Fluorophenyl) (3.15 g, 7.87 mmol) in DME (40.0 mL) under a nitrogen atmosphere. Methyl vinyl ketone (1.30 mL, 15.8 mmol) was added dropwise. After about 47 h, the volatiles were removed under reduced pressure to afford 10-bromo-1-(4-fluorophenyl)-6-oxo-5-(3-oxobutyl)-5,6,7,8-tetrahydro-1H-oxepino[3,2-f]indazole-5-carbonitrile as a tan foam. LC/MS, method 3, Rt=2.33 min, MS m/z 470 and 472 (M+H)+. The material was dissolved in toluene (80 mL) in a 250 mL round bottom with Dean-Stark trap and reflux condenser attached under a nitrogen atmosphere. Toluene-4-sulfonic acid hydrate (0.599 g, 3.15 mmol) was added. After about 3 h at reflux, the mixture was allowed to cool to rt. Sat. aq. NaHCO3 (100 mL) was added.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: BrCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: BrCCCCCCOc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.4 %

Procedure:
A mixture of 4-bromophenol (10 g), 1,6-dibromohexane (49.4 g) and potassium carbonate (9.59 g) in N,N-dimethylformamide (50 ml) was stirred for 4 hours at 60° C. (bath temp.), and then cooled to ambient temperature. To the reaction mixture was added ethyl acetate (200 ml), and the mixture was washed with water (200 ml×2) and brine. The organic layer was dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give a crude product. The crude product was purified by silica gel chromatography (1:0-1:1 hexane-ethyl acetate) to give 1-bromo-4-(6-bromohexyloxy)benzene (15.61 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Cl:7])[N:6]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[S:3][C:4]([CH2:8][OH:9])=[C:5]([Cl:7])[N:6]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a 0° C. solution of 2,4-dichloro-1,3-thiazole-5-carbaldehyde (1.0 g, 5.5 mmol) in anhydrous methanol (45 mL) was added sodium borohydride (340 mg, 9.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added and the methanol was evaporated. The resultant mixture was extracted with EtOAc (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, to afford (2,4-dichloro-1,3-thiazol-5-yl)methanol (850 mg, 84% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2>C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCNCC4)ccc3o2)cc(Cl)c2[nH]ccc12

Procedure:
A solution of tert-butyl 4-[(2-{4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-cyanopyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate (176 mg, 0.29 mmol) in CH2Cl2 (4 mL) and trifluoroacetic acid (2 mL) was stirred at room temperature for 4 h and concentrated to provide 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-[5-(piperazin-1-ylmethyl)-1-benzofuran-2-yl]nicotinonitrile as a yellow solid in quantitative yield (182 mg). HPLC retention time: 6.5 min.(g); MS: 497.3 (M+H); and HRMS: 497.1851.