Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2>C(Cl)Cl>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([O:18][CH3:19])=[O:17])[NH:11]2
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1cc2c(O)cccc2[nH]1
Temperature: -78 °C
Yield: 64 %

Procedure:
Boron tribromide (73.1 ml, 1.0 M solution in DCM) was added dropwise to a solution of methyl 4-methoxyindole-2carboxylate (5 g) in DCM (200 ml) cooled to −78° C. under argon. The reaction was allowed to warm to room temperature then partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-50% ethyl acetate as eluent to give the end product as a yellow solid (2.98 g, 64%); NMR δ(CD3SOCD3) 3.82 (s, 3H), 6.36 (d, 1H), 6.85 (d, 1H), 7.02 (t, 1H), 7.17 (d, 1H), 9.66 (s, 1H), 11.72 (bs, 1H); M/z (+) 192 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:13][C@:12]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)([CH3:14])[N:11]([CH2:23][C:24]#[C:25][C:26]2[CH:27]=[C:28]3[CH2:43][C@@:33]4([C:41]5[C:36](=[N:37][CH:38]=[CH:39][CH:40]=5)[NH:35][C:34]4=[O:42])[CH2:32][C:29]3=[N:30][CH:31]=2)[C:10](=[O:44])[C:5]21[CH2:9][CH2:8][CH2:7][CH2:6]2.C(O)(C(F)(F)[F:48])=O>C(#N)C.[Ag]F>[F:21][C:19]1[CH:20]=[C:15]([C@@:12]2([CH3:14])[N:11]([CH2:23][C:24]#[C:25][C:26]3[CH:27]=[C:28]4[CH2:43][C@@:33]5([C:41]6[C:36](=[N:37][CH:38]=[CH:39][CH:40]=6)[NH:35][C:34]5=[O:42])[CH2:32][C:29]4=[N:30][CH:31]=3)[C:10](=[O:44])[C:5]3([CH2:6][CH2:7][CH2:8][CH2:9]3)[N:4]([CH2:3][CH2:2][F:48])[CH2:13]2)[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@]1(c2cc(F)cc(F)c2)CN(CCCl)C2(CCCC2)C(=O)N1CC#Cc1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: F[Ag]
Solvent: CC#N
Product: C[C@@]1(c2cc(F)cc(F)c2)CN(CCF)C2(CCCC2)C(=O)N1CC#Cc1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of (6S)-3-{3-[(8R)-6-(2-chloroethyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5] dec-9-yl]prop-1-yn-1-yl}-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (67 mg, 0.11 mmol) and silver(I)fluoride (140 mg, 1.1 mmol) in acetonitrile (3 ml) was heated at 100° C. for 90 min The mixture was diluted with TFA (0.5 mL), filtered, and purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The desired fractions were poured onto saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound. MS: m/z=600 (M+1). HRMS: m/z=600.2604 (M+1); calculated m/z=600.2581 (M+1) for C34H34F3N5O2.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]=[N:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C>>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[C:22]#[N:23])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: CSc1ccc(N=Cc2ccc(F)cc2)cc1
Product: CSc1ccc(NC(C#N)c2ccc(F)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-fluorobenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale yellow powder (yield 96%).
Reaction SMILES: N1C=CN=C1.[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[I:23]I.C(OCC)(=O)C.ClCCl>ClCCl>[C:6]([O:10][C:11](=[O:22])[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][I:23])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCc1cccc(CO)c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cccc(CI)c1
Reaction time: 16 h
Yield: 119.7 %

Procedure:
Stir polystyrene-bound triphenylphosphine (4.27 g, 12.8 mmol) and imidazole (0.86 g, 12.7 mmol) in dichloromethane (45 mL). Add a solution of (3-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (1.70 g, 6.1 mmol) in dichloromethane (45 mL). Add iodine (3.22 g, 12.7 mmol) in 3 portions. Stir 16 hrs. Filter through a pad of diatomaceous earth. Wash with aqueous sodium thiosulfate. Dry the organic portion over sodium sulfate. Filter and concentrate. Chromatograph the residue on silica eluting with 25% ethyl acetate/dichloromethane to provide the title compound (2.53 g, 7.3 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][CH2:36][O:37]C1CCCCO1.O>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][CH2:36][OH:37])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC[C@H](c2cccc(O)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: O=C1NC[C@H](c2cccc(OCCO)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-hydroxyphenyl)-imidazolidin-2-one (26 mg, 0.068 mmol) in acetonitrile (2 mL) is added Cs2CO3 (50 mg, 0.15 mmol) followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (30 mg, 0.14 mmol). The resulting mixture is stirred at room temperature for 24 h and is then treated with water (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers are concentrated and the residue is dissolved in MeOH (1 mL). To the MeOH solution is added catalytic amount of pTSA (˜1 mg). The resulting mixture is stirred at room temperature for 1 h and is then treated with sat. NaHCO3 solution (3 mL). After extracting with EtOAc (3×3 mL), the combined organic layers are concentrated and purified by preparative thin layer chromatography (silica gel, 85% EtOAc/hexane) to provide the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.33 (d, J=9.2 Hz, 2H), 7.22-7.27 (m, 3H), 6.89 (d, J=7.6 Hz, 1H), 6.81-6.88 (m, 6H), 5.23 (dd, J=8.8, 6.0 Hz, 1H), 4.90 (br s, 1H), 3.92-4.08 (m, 5H), 2.34 (dd, J=8.8, 6.4 Hz, 1H), 2.03 (t, J=5.6 Hz, 1H); HPLC-MS calculated for C23H21ClN2O4 (M+H+) 425.1, found 425.1.
Reaction SMILES: [CH3:1][C:2](=[CH2:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[S:9]1C=CC=C1CC(O)=O.[CH3:18][CH2:19][O:20]CC>>[C:19]([S:9][CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:20])[CH3:18]
Reactant: O=C(O)Cc1cccs1
Reactant: CCOCC
Reactant: C=C(C)C(=O)OCC
Product: CCOC(=O)C(C)CSC(C)=O
Temperature: 65 °C
Reaction time: 36 h

Procedure:
Ethyl 2-methylpropenoate (39 mmol) was diluted with 5.6 mL (78 mmol) of thiolacetic acid and stirred at 65° C. for 36 h. The mixture was then diluted with ether, washed with water and the organic phase was dried with Na2SO4. Evaporation to dryness yielded the title material as an orange oil which was used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([O:34][CH3:35])[CH:33]=1)[NH2:30].C(O)(=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH3:24])[C:12]2[N:13]=[C:14]([NH:30][C:29]3[CH:31]=[C:32]([O:34][CH3:35])[CH:33]=[C:27]([O:26][CH3:25])[CH:28]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1cc(N)cc(OC)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc(OC)c1
Temperature: 160 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-2-methanesulfonyl-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 39 and 0.400 g (2.60 mmol) of 3,5-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. At ca. 100° C., 1 mL of glacial acetic acid was added to the melt to dissolve. Water (10 mL) was added to precipitate a gum. Decanted and dissolved gum in 35 mL of methylene chloride. The solution was washed with 2×20 mL of water, dried over magnesium sulfate, charcoaled, filtered, and concentrated. The remaining gum was purified silica gel chromatography eluting with chloroform and then with 2:1 hexane:ethyl acetate to obtain the fraction containing the pure product. The eluent was evaporated to near dryness when crystals separated. The crystals were filtered and washed with 0.5 mL of ether; wt 0.059 g; mp 228°-230° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([C:12]3[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:9][N:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:22][C:21]([F:24])([F:23])[C:20]1[C:12]([C:8]2[N:7]=[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([NH:25][C:26]4[CH:31]=[N:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=4)[C:11]3=[N:10][CH:9]=2)=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([NH2:18])=[O:17]
Reactant: NC(=O)c1cnc(-c2cnc3c(Cl)ccnc3n2)c(C(F)(F)F)c1
Reactant: Nc1cnc(C(F)(F)F)cn1
Product: NC(=O)c1cnc(-c2cnc3c(Nc4cnc(C(F)(F)F)cn4)ccnc3n2)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 6-(8-chloropyrido[2,3-b]pyrazin-3-yl)-5-(trifluoromethyl)nicotinamide (70.6 mg, 0.2 mmol) and 2-amino-5-trifluoromethyl-pyrazine (98.4 mg, 0.6 mmol) in a screw cap vial at 140° C. for 20 hours under N2 atmosphere. Purify the reaction mixture by column chromatography using EtOAc to 1% MeOH/EtOAc as eluent to afford the title compound as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.182 (s, 1H), 9.456 (s, 1H), 9.44(s, 1H), 9.074 (d, 1H, J=1.3 Hz), 9.052 (s, 1H), 8.87(d, 1H, J=1.3 Hz), 8.828 (d, 1H, J=2.6 Hz), 8.542 (s, 1H), 7.974 (1, 1H). MS=481.42 (M+H). The IC50 determined as described in Example 6 is less than 1 micromolar.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>ClCCl>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCCCN1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
To a solution of N-3-aminopropylpiperidine (1.4 g, 10 mmol) in dichloromethane (20 mL) was added DIEA (1.9 mL, 11 mmol) followed by slow addition of 4-methoxy benzoyl chloride (1.9 g, 11 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was washed with 1 N KOH (aq.) (1×20 mL) and brine (1×20 mL). The organic phase was dried (K2CO3) and concentrated in vacuo to afford 4-methoxy-N-(3-piperidin-1-ylpropyl)benzamide (1.9 g, 6.9 mmol, 69%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][O:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH:16]=[C:17]([C:23](O)=[O:24])[NH:18]4)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[ClH:26].Cl.Cl.[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH2:46])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1>>[ClH:26].[ClH:26].[C@H:29]1([CH2:39][N:40]2[CH2:45][CH2:44][CH:43]([NH:46][C:23]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[C:14]([O:13][CH2:12][C:8]3[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=3)[CH:22]=[CH:21][CH:20]=4)=[O:24])[CH2:42][CH2:41]2)[C@@H:38]2[N:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)[CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Reactant: COc1cccc2c(COc3cccc4[nH]c(C(=O)O)cc34)coc12
Agent: Cl
Product: COc1cccc2c(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)coc12

Procedure:
This compound is synthesized from 4-(7-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (119) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:21])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[CH:13]=[N:12]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C=O.[OH-].[Na+].Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[C:35](=O)(O)[O-:36].[Na+]>CN(C=O)C>[C:31]([O:30][C:28](=[O:29])[CH2:27][O:20][C:17]1[C:18]([CH2:35][OH:36])=[C:19]2[C:14]([CH:13]=[N:12][N:11]2[CH2:10][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH3:21])=[CH:15][CH:16]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C([O-])O
Reactant: C[C@H](Cn1ncc2ccc(O)cc21)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CO)c21)O[Si](C)(C)C(C)(C)C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a mixture of 1-[(R)-2-(tert-Butyldimethylsilanyloxy)-propyl]-1H-indazol-6-ol (3.06 g, 10 mmol) in DMF (60 mL) was added formaldehyde (37%, 2.43 mL, 30 mmol) and 2 N NaOH (10 mmol). The mixture was stirred overnight and t-butyl bromoacetate (2.42 mL, 2.93 g, 15 mmol) was added. After 1 h the mixture was mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 5% to 25% ethyl acetate in hexane) gave an oil (2.87 g, 64%): LC/MS (+APCI) m/z 451(M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[F:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[N:18]=5)=[CH:14][C:9]=4[N:8]=[C:7]3[C@@H:27]3[C@H:29]([C:30]([OH:32])=[O:31])[C:28]3([CH3:36])[CH3:35])[CH:3]=2)=[CH:43][CH:42]=1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(F)cc3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 4-fluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H30FN3O3, 571.23; m/z found, 572.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=8.5, 1H), 8.12 (d, J=8.5, 1H), 7.86 (d, J=8.2, 1H), 7.80-7.74 (m, 1H), 7.71 (d, J=8.4, 1H), 7.61-7.55 (m, 1H), 7.54-7.50 (m, 1H), 7.46-7.39 (m, 3H), 7.37-7.34 (m, 1H), 7.33-7.30 (m, 1H), 7.29-7.26 (m, 1H), 7.17-7.08 (m, 3H), 7.01-6.97 (m, 1H), 5.54-5.37 (m, 4H), 2.34-2.30 (m, 1H), 2.15 (d, J=8.2, 1H), 1.18 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([C:21](O)=[O:22])=[CH:19][O:20][C:15]=2[CH:14]=1>>[OH:12][C:13]1[CH:25]=[CH:24][C:16]2[O:17][C:18]([C:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:22])=[CH:19][O:20][C:15]=2[CH:14]=1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Reactant: CCCCNc1ccccc1
Product: CCCCN(C(=O)C1=COc2cc(O)ccc2O1)c1ccccc1
Yield: 91 %

Procedure:
That compound is obtained in a yield of 91% starting from N-butylaniline and 6-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>O1CCCC1>[F:28][C:27]([F:29])([F:30])[C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)N1CCN(c2ccc(O)cc2)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(COc2ccc(N3CCNCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(4-hydroxy-phenyl)-piperazine-1-carboxylic acid tent-butyl ester (1.5 g, 5.4 mmol) in dry tetrahydrofuran (5 mL) was added to a suspension of sodium hydride (431 mg, 60% in oil, 10.8 mmol) in dry tetrahydrofuran (35 mL). After 15 min, a solution of 1-bromomethyl-4-trifluoromethyl-benzene (1.9 g, 8.1 mmol) in tetrahydrofuran (5 mL) was added. The mixture was stirred for 16 hr at room temperature, filtered, and concentrated under vacuum. The resulting residue was diluted in ethyl acetate (40 mL), and the organic layer was washed with water (3×20 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (30 mL). The mixture was then stirred for 30 min. Afterward, the mixture was concentrated under vacuum, taken up in dichloromethane (30 mL), and evaporated to dryness. The resulting residue was diluted in diethylether (5 mL) and then combined with a molar solution of HCl in diethylether (10 mL, 1M). A precipitate formed, which was filtered, washed with diethylether (10 mL), and dried under vacuum. The desired product was isolated as a hydrochloride salt with traces of solvent.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].[Cu](C#N)[C:13]#[N:14].CCOCC>CN(C=O)C>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][C:5]=1[OH:11])[C:13]#[N:14])(=[O:3])[CH3:1]
Reactant: N#C[Cu]C#N
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(=O)c1cc(C#N)ccc1O
Temperature: 160 °C
Yield: 70.1 %

Procedure:
A solution of 5-bromo-2-hydroxyacetophenone (11, 10.00 g, 46.5 mmoles) in anhydrous DMF (25 mL) was mixed with copper cyanide (6.25 g, 69.75 mmoles) and the resulting reaction mixture was heated for about 8 to 16 hours at a temperature of about 160° C. The reaction mixture was cooled to room temperature and mixed with ether, the ether mixture was filtered through celite and the filtrate concentrated to afford a solid which was purified by flash column chromatography through silica using Hexane/EtOAc (4:1) as eluant to yield compound 12 as a clear colorless oil (5.25 g, 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][CH:9]=[C:8]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:7]=1)=[O:5])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(O)(C(F)(F)F)=O>[O:16]=[C:14]1[C:9]2[NH:10][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][C:8]=2[CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)c1cc(CCCC(=O)O)c[nH]1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2c([nH]1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Into a 1000-mL round-bottom flask was placed a solution of 113h (30 g, 133.19 mmol, 1.00 equiv) in CF3COOH (500 mL) and trifluoroacetyl 2,2,2-trifluoroacetate (42 g, 199.97 mmol, 1.50 equiv). See FIG. 14. The resulting solution was stirred at room temperature for 60 min, concentrated under vacuum, diluted with 500 mL of water and 500 mL of EA, and extracted with 3×500 mL of ethyl acetate. The combined organic layers were washed with 1×500 mL of saturated aqueous potassium carbonate and 1×500 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to afford 24 g (87%) of 113i as a light brown solid.
Reaction SMILES: [CH2:1]([Zn]CC)C.FC(F)(F)C(O)=O.ICI.[CH2:16]([O:23][C:24]([NH:26][C@@:27]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][C:31](=[CH2:33])[C@@H:30]2[C@H:28]1[C@H:29]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>ClC(Cl)C>[CH2:16]([O:23][C:24]([NH:26][C@@:27]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:32][C:31]2([CH2:1][CH2:33]2)[C@@H:30]2[C@H:28]1[C@H:29]2[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C1C[C@@](NC(=O)OCc2ccccc2)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: CC[Zn]CC
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Solvent: ICI
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OCc1ccccc1)(C(=O)OCC)CC21CC1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a jacketed reaction flask connected to a chiller unit, add diethylzinc solution (157.2 mL, 157.2 mmol, 1M in heptanes) under a nitrogen atmosphere. Cool the solution to −15° C. and dilute with cold (−15° C.), dry dichloroethane (157.2 mL). Dissolve trifluoroacetic acid (11.1 mL, 146.7 mmol) in dichloroethane (11.1 mL) and add to the reaction vessel over 50 minutes, keeping the internal temperature below −10° C. Stir the resulting suspension at −10 to −15° C. for 30 minutes. Dissolve diiodomethane (12.7 mL, 42.1 g, 157.2 mmol) in dichloroethane (12.7 mL) and add to the reaction mixture over 50 minutes, keeping the internal temperature below −10° C. Stir the resulting thin, white suspension at −10 to −15° C. for 30 minutes. Dissolve diethyl (1S,2S,5R,6S)-2-benzyloxycarbonylamino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (20.3 g, 87.9% potency, 46.0 mmol) in dichloroethane (30.4 mL) and add to the reaction mixture over 10 minutes, keeping the internal temperature below −10° C. Stir the clear, pale yellow solution at −10° C. for 5 minutes and monitor for latent exotherms. Change the set point on the chiller to 0° C. and stir the reaction mixture at that temperature for 48 hours. Quench the reaction mixture by addition of 5N HCl (62.9 mL, 314.4 mmol) over 15 minutes, keeping the internal temperature below 6° C. Stir the resulting mixture at 0-5° C. for 20 minutes, then transfer to a funnel and separate the layers. Wash the organic layer with 1N HCl (2×50 mL) followed by 1:1 saturated NaHCO3/H2O (60 mL), 1:1 saturated Na2CO3/H2O (60 mL) and water (50 mL). Dry the organics over Na2SO4 and concentrate in vacuo to afford the title compound as a pale yellow oil (19.6 g, 60.3% potent, 63.9% corrected yield). 1H NMR (DMSO-d6) δ 0.37 (m, 2H), 0.52-0.55 (dm, 2H), 1.13-1.17 (m, 6H), 1.49-1.50 (m, 1H), 1.51-1.56 (m, 1H), 1.60-1.79 (m, 2H), 3.97-4.10 (m, 5H), 5.00 (s, 2H), 7.29-7.34 (m, 5H), 8.04 (s, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH:25]([CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)=O>C(Cl)Cl>[Br:21][C:20]([Br:24])=[CH:25][CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1
Reactant: O=CC1CCC(=O)CC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCC(C=C(Br)Br)CC1
Reaction time: 0.17 h
Yield: 85.8 %

Procedure:
A solution of 36.72 g of triphenylphosphine in 200 ml of methylene chloride was treated slowly at -20° C. with 23.22 g of carbon tetrabromide and stirred for a further 10 minutes. Subsequently, the mixture was added dropwise by means of a cannula to a solution, cooled to -60° C., of 6.30 g of 4-formylcyclohexanone in 100 ml of methylene chloride. The mixture was stirred at -60° C. for a further 15 minutes and then partitioned in water/methylene chloride. The aqueous phases were extracted a further twice with methylene chloride. The organic phases were washed twice with water, dried over magnesium sulphate and evaporated. Low-pressure chromatography of the resulting, pale yellow oil (16 g) on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 12.08 g (85.8%) of 4-(2,2-dibromovinyl)cyclohexanone as a pale yellow liquid.