Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1([N:19]2[CH2:28][C@H:27]([F:29])[CH2:26][C@H:20]2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][C:43]([F:46])([F:45])[F:44])[CH:33]=1>>[CH2:1]([C:8]1([N:19]2[CH2:28][C@H:27]([F:29])[CH2:26][C@H:20]2[C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]([S:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH3:30])=[CH:33][C:34]=2[O:42][C:43]([F:44])([F:45])[F:46])(=[O:40])=[O:39])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](F)CN1C1(Cc2ccccc2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(Cc3ccccc3)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 47.8 %

Procedure:
With 87 mg of the compound obtained in Step 30-2 and of 74 mg 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 67 mg of the title compound (colorless solid) was obtained by a similar method to Example 2.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[C:8]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:9]=3[S:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:35]([C:37]1[N:38]=[CH:39][N:40](C(OC(C)(C)C)=O)[CH:41]=1)=[CH2:36]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:8]2[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2](/[CH:36]=[CH:35]/[C:37]4[N:38]=[CH:39][NH:40][CH:41]=4)=[CH:3][CH:4]=3)=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:10][C:9]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Reactant: C=Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(/C=C/c3c[nH]cn3)cc2)cc1
Temperature: 150 °C
Yield: 79.6 %

Procedure:
To a microwave vial, 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (50 mg, 0.113 mmol) was dissolved in DMF (2 mL) and triethyl amine (0.474 mL, 3.40 mmol). To the solution was added tert-butyl 4-vinyl-1H-imidazole-1-carboxylate (66.0 mg, 0.340 mmol) and Pd(PPh3)2Cl2 (7.95 mg, 0.011 mmol). The system was flushed with nitrogen and heated at 150° C. for 1 h under microwave radiation. The mixture was cooled to room temperature and diluted with DCM and sat. NH4Cl. The organic layer was collected (phase separator) and concentrated onto silica gel and the material was purified by column chromatography (SiO2, 0-30% DCM/MeOH) to afford (E)-4-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)styryl)-1H-imidazole (41 mg, 0.090 mmol, 80% yield) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.78 (d, J=1.52 Hz, 1H), 7.51-7.62 (m, 2H), 7.46-7.51 (m, 1H), 7.39 (d, J=9.09 Hz, 2H), 7.32 (d, J=2.53 Hz, 1H), 7.15 (d, J=9.09 Hz, 1H), 7.08 (d, J=16.67 Hz, 1H), 6.76-6.95 (m, 6H), 3.77 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:13](=[O:14])[C:12]2C(C(O)=O)=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:9]1=[O:36].CN(C)C=O>ClCCl>[CH3:7][N:8]1[C:13](=[O:14])[C:12]2[C:1]([C:2]([Cl:4])=[O:3])=[C:16]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[S:17][C:11]=2[N:10]([CH2:32][CH:33]([CH3:34])[CH3:35])[C:9]1=[O:36]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)Cl)c(Cc3cccc4ccccc34)sc21
Reaction time: 2 h

Procedure:
Oxalyl chloride (0.092 ml) was added to a solution of 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid (Example 15a, 222 mg) and dimethylformamide (0.01 ml) in anhydrous dichloromethane (5 ml) at room temperature. After 2 hours, the solution was evaporated under reduced pressure to give 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carbonyl chloride as an oil. A solution of this oil (58 mg) in anhydrous dichloromethane (2 ml) was added to a stirred mixture of glycine methyl ester hydrochloride (29 mg) and triethylamine (0.037 ml) in anhydrous dichloromethane (1 ml) at room temperature. After 1 hour, ethyl acetate (25 ml) and 2M hydrochloric acid were added. The organic layer was washed with water then with saturated sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure The residue was dissolved in a mixture of tetrahydrofuran (4 ml), methanol (2 ml) and 1M sodium hydroxide solution (1 ml). After 2 hours, water (20 ml) was added and the solution was extracted with ether (20 ml). The aqueous layer was acidified with hydrochloric acid and then extracted with ethyl acetate (3×20 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was recrystallised from ethyl acetate:isohexane to give the title compound (42 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:39]=[CH:38][C:22]([C:23]([N:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]3[CH:35]=[CH:36][CH:37]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[CH:35]1[N:28]2[C:29]3[C:34]([N:25]([C:23]([C:22]4[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]5[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=5[CH3:1])=[CH:39][CH:38]=4)=[O:24])[CH2:26][C:27]2=[CH:37][CH:36]=1)=[CH:33][CH:32]=[CH:31][CH:30]=3
Reactant: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 1.5 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 3 mmol of triethylamine. After stirring for 15 minutes, 1.5 mmol of 4,5-dihydro-5-(4-aminobenzoyl)pyrrolo[1,2-a]quinoxaline is added and the mixture stirred for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography to give the desired product as a solid, m.p. 206°-207° C.
Reaction SMILES: [OH-:1].[Li+].OO.[O-]O.[Li+].C([C@@H]1COC(=O)N1[C:21](=[O:40])[C@@H:22]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=1)[CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)C1C=CC=CC=1>O.O1CCCC1>[Cl:39][C:31]1[CH:30]=[C:29]([C@@H:22]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[C:21]([OH:40])=[O:1])[CH:34]=[CH:33][C:32]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: [OH-]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1Cl
Agent: OO
Agent: [Li+]
Agent: [O-]O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
A solution of lithium hydroxide (215 mg, 9.0 mmol) in water (2.8 mL) was treated with a 30% aqueous hydrogen peroxide solution (2.0 mL, 18 mmol). This freshly prepared lithium hydroperoxide solution was then cooled to 0° C. and then slowly added to a cooled (0° C.) solution of the 4(R)-benzyl-3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionyl]-oxazolidin-2-one (2.20 g, 4.5 mmol) in tetrahydrofuran (18 mL) and water (5.8 mL). After 1.5 h at 0° C., the reaction mixture was quenched with a 1.5N aqueous sodium sulfite solution (25 mL) and then diluted with water (150 mL). The aqueous layer was extracted with diethyl ether (3×50 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution to pH=2 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 75/25 hexanes/ethyl acetate with 1% acetic acid) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (1.26 g, 85%) as a white solid: mp 106.1-108.8° C.; [α]23599=−43.0° (c=0.172, chloroform); EI-HRMS m/e calcd for C15H19ClO4S (M+) 330.0692, found 330.0690.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[I:12])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[C:6]([I:12])[CH:7]=1
Reactant: [N-]=[N+]=NCc1ccc(F)cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NCc1ccc(F)cc1I
Temperature: 55 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
A solution of 1-(azidomethyl)-4-fluoro-2-iodobenzene (15.2 g, 54.8 mmol) in DMF (35 ml) at 0° C. was treated with triphenylphosphine (21.6 g, 81.2 mmol) and then stirred for 1 h. The reaction mixture was then treated with water (5 ml) and heated at 55° C. for 1 h. The DMF was concentrated in vacuo and the residue was diluted with ethyl acetate (200 ml). The organic phase was extracted with 0.5 N hydrochloric acid (140 ml) and the aqueous extract was washed with ethyl acetate. The aqueous phase was then adjusted to pH 9 with 1 N LiOH and extracted with ethyl acetate (2×200 ml). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated. The residue was diluted with ether (200 ml), filtered and concentrated. Distillation of the residue in vacuo gave 8.52 g (62% yield) of the title amine as a clear oil: bp 85° C./0.35 torr (bulb to bulb distillation air bath temperature). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 3.64 (2H, s, CH2), 7.27 (1H, m, aromatic), 7.53 (1H, dd, J=6 Hz and J=8.6H, aromatic), 7.83 (1H, dd, J=3 Hz and J=8 Hz, aromatic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:22][CH2:23][Cl:24])[CH2:19][CH2:20][Cl:21])=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:24][CH2:23][CH2:22][N:18]([CH2:19][CH2:20][Cl:21])[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[NH:8][C:4]2[CH:3]=[C:2]([NH:1][C:27](=[O:28])[CH2:26][Cl:25])[CH:7]=[CH:6][CH:5]=2)=[CH:13][CH:14]=1
Reactant: Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)Nc1cccc(NC(=O)Nc2ccc(N(CCCl)CCCl)cc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 46a (3.0 g, 8.0 mmol) in THF (100 mL), chloroacetyl chloride (2.2 g, 20 mmol) in THF (50 mL) was added dropwise at RT and the resulting mixture was stirred at RT for additional 45 minutes. The reaction mixture was evaporated under reduced pressure and the solid residue was triturated with saturated aqueous solution of NaHCO3 and then filtered. The solid was washed successfully with water and hexane, and dried to yield N-(3-(3-(4-(bis(2-chloroethyl)amino)-phenyl)ureido)phenyl)-2-chloroacetamide, 2.8 g (82%); mp 232-233° C. 1H NMR (DMSO-d6) δ: 2.80-2.83 (2H, t, J=5.9 Hz, CH2), 3.68-3.71 (8H, m, CH2), 3.86-3.89 (2H, t, J=5.9 Hz, CH2), 6.70-6.72 (2H, d, J=8.5 Hz, Ar—H), 7.14-7.30 (5H, m, Ar—H), 7.76 (1H, s, Ar—H), 8.46 (1H, brs, NH), 8.73 (1H, brs, NH), 10.04 (1H, brs, NH).
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17](=O)/[CH:18]=[CH:19]/[N:20](C)C)=[N:11]2)[CH:7]=[CH:8][CH:9]=1.[F:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][CH:30]=[C:29]2[NH:36]N>>[F:1][CH:2]([F:24])[O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[C:12]([C:17]3[N:36]([C:29]4[C:28]5[C:33](=[CH:34][CH:35]=[C:26]([F:25])[CH:27]=5)[N:32]=[CH:31][CH:30]=4)[N:20]=[CH:19][CH:18]=3)=[N:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)F)c2)ccc1=O
Reactant: NNc1ccnc2ccc(F)cc12
Product: O=c1ccn(-c2cccc(OC(F)F)c2)nc1-c1ccnn1-c1ccnc2ccc(F)cc12

Procedure:
The product was obtained starting from 1-(3-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-10) and (6-fluoro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=450.1 (M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]1[C:11](=[O:12])[CH:10]=[CH:9][CH2:8]1.[CH:13]1[C:14](/[CH:29]=[N:30]/[OH:31])=[CH:15][CH:16]=[N+:17]([CH2:19][N+:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[N:27]/[OH:28])=[CH:22][CH:21]=2)[CH:18]=1.[Br-:32].[Br-].[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[C:11](=[O:12])[CH2:10][CH2:9][CH:8]=2)(=[O:42])=[O:41])=[CH:36][CH:35]=1.[CH:15]1[C:14](/[CH:29]=[N:30]/[OH:31])=[CH:13][CH:18]=[N+:17]([CH2:19][N+:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[N:27]/[OH:28])=[CH:24][CH:25]=2)[CH:16]=1.[Br-:32].[Br-:32]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1C=CCC1CCCCCO
Agent: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2=CCCC2=O)cc1

Procedure:
Treatment of 2-(hydroxypentyl)-2-cyclopentenone methoxime (Example 25) with p-toluenesulfonyl chloride in pyridine in the manner described in Example 18 gives a colorless oil. IR (film) 1600, 1190, 1180, 1050, 885 cm-1.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]([O:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)C(C)C.C([Sn](Cl)(Cl)CCCC)CCC.[C:35]1([SiH3])[CH:40]=[CH:39][CH:38]=[CH:37]C=1>C1COCC1>[CH:37]1([N:14]2[CH2:13][CH2:12][CH:11]([O:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:18][CH:17]=3)[CH2:16][CH2:15]2)[CH2:38][CH2:39][CH2:40][CH2:35]1
Reactant: c1cn(-c2ccc(OC3CCNCC3)cc2)cn1
Reactant: [SiH3]c1ccccc1
Agent: CC(C)C=O
Agent: CCCC[Sn](Cl)(Cl)CCCC
Solvent: C1CCOC1
Product: c1cn(-c2ccc(OC3CCN(C4CCCC4)CC3)cc2)cn1
Reaction time: 16 h

Procedure:
A solution of the product of Example 6 (130 mg), isobutyraldehyde (0.06 mL), and dibutyltin dichloride (3 mg) in THF (0.1 mL) was treated with phenylsilane (0.07 mL). After 16 h, the resulting mixture was chromatographed (0–8% 2M methanolic ammonia/DCM), giving the title compound as a waxy solid (57 mg). 1H NMR (400 MHz, CDCl3): 7.75 (t, J=1.2 Hz, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.20 (t, J=1.2 Hz, 1H), 7.17 (t, J=1.2 Hz, 1H), 6.99 (d, J=9.0 Hz, 2H), 4.39–4.29 (m, 1H), 2.87–2.77 (br m, 1H), 2.57–2.48 (m, 1H), 2.40–2.30 (m, 2H), 2.08–1.99 (m, 2H), 1.94–1.82 (m, 5H), 1.75–1.64 (m, 2H), 1.61–1.61 (m, 2H), 1.47–1.37 (m, 2H).
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10](O)=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.S(Cl)([Cl:21])=O>ClCCl.CN(C)C=O>[C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][O:8][CH2:9][C:10]([Cl:21])=[O:11])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12
Reactant: O=S(Cl)Cl
Reactant: O=C(O)COCCN1C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)COCCN1C(=O)c2ccccc2C1=O
Reaction time: 48 h

Procedure:
To a suspension of 6 g of 2-(phthalimido)ethoxyacetic acid in dichloromethane are added 2.05 ml of thionyl chloride and 3 drops of dimethylformamide, and the mixture is stirred for 2 days. The solvent is distilled off to give 2-(phthalimido)ethoxyacetyl chloride. A solution of 2-(phthalimido)ethoxyacetyl chloride in 10 ml of dichloromethane is added dropwise to a solution, maintained at -5° C., of 3.6 g of Meldrum's acid in 20 ml of dichloromethane and 4.3 ml of pyridine. Then, the mixture is stirred overnight at room temperature. To the resultant mixture is added 2 normal hydrochloric acid and the dichloromethane layer is extracted. The extract is washed with sodium chloride solution three times, dried over sodium sulfate and the solvent is distilled off. To the residue is added 50 ml of isopropyl alcohol and refluxed for 5 hours. The solvent is distilled off and the residue is purified by column chromatography on silica gel to give 3.7 g of isopropyl 4-[2-(phthalimido)ethoxy]-3-oxobutylate.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]2[CH:17]=[CH:16][C:15]([S:29][C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[C:14]([NH:13][C:2]3[C:3]4[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=4)[N:9]=[CH:10][CH:11]=3)[CH:19]=2)=[CH:23][CH:24]=1
Reactant: Nc1cc(OCc2ccc(F)cc2)ccc1Sc1ccc(O)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: Cc1ccc2c(Nc3cc(OCc4ccc(F)cc4)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 1d (53 mg, 0.30 mmol) was reacted with 4-[2-amino-4-(4-fluoro-benzyloxy)-phenylsulfanyl]-phenol (102 mg, 0.30 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (115 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 5.11 (s, 2 H) 6.26 (d, J=6.99 Hz, 1 H) 6.65 (d, J=8.46 Hz, 2 H) 7.10 (d, J=8.82 Hz, 2 H) 7.15-7.27 (m, 4 H) 7.49 (m, J=5.88 Hz, 2 H) 7.81 (d, J=8.46 Hz, 1 H) 8.40 (d, J=6.98 Hz, 1 H) 8.98 (d, J=8.46 Hz, 1 H) 9.78 (s, 1 H) 11.03 (br s,1 H) 14.36 (br s, 1 H); MS (ESI+) m/z, 484 (M+H−TFA)+; (ESI−) m/z, 482 (M−H−TFA)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Cc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)propan-2-one (2.2 g, 0.01 mol) in dimethylformamide (10 mL) was added 1,3-dibromopropane (7.6 mL, 0.07 mol), potassium carbonate (2.3 g, 0.01 mol) and potassium iodide (0.7 g, 0.004 mol). The mixture was stirred at room temperature for 72 hours. Water was added into the reaction vessel and the crude was extracted with ethyl acetate. The organic layer was washed with water and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 100% to 10%), obtaining the title compound (54%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]#[N:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](=O)CCCC)CCC.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:35][N:34]=[N:33][N:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCCC(c2nnn[nH]2)C1
Temperature: 95 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
To a mixture of 3-cyano-piperidine-1-carboxylic acid benzyl ester (1 g, 4.1 mmol), and dibutyltinoxide (153 mg, 0.6 mmol) in toluene (8 mL) is added trimethylsilylazide (1.1 mL, 8.2 mmol) at room temperature. After the mixture is heated at 95° C. for 15 h, more trimethylsilylazide (2 mL, 15 mmol) is added and the stirring is continued for 6 h at 95° C. The mixture is concentrated, and the resulting solid is triturated with heptane (30 mL) and filtered to afford 3-(1H-tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester (1 g). LCMS: RT=2.31 minutes, MS: 288 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]([CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CC1CC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCN(C(=O)OC(C)(C)C)C1CC(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methyl 2-(3-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino) cyclobutyl)acetate from step 2 in a mixture of MeOH and H2O was added 1N NaOH (8 mL). The resultant reaction mixture was stirred at RT overnight. Half of the solvents were removed under reduced pressure and 1N HCl was added to adjust pH of the solution to 4. The aqueous phase was extracted with EtOAc for three times. The combined organic phase was then dried and concentrated in vacuo to afford the acid (0.9 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1.[N+:25](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-:26].C(O[K])(C)(C)C.O>COCCOC>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:26]#[N:25])[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: COCCOC
Product: N#CC(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
At 0° C. to a solution of bis(3-(trifluoromethoxy)phenyl)methanone (3 g, 8.6 mmol), prepared as described in Procedure 11, in DME (60 mL) was added 1-(isocyanomethylsulfonyl)-4-methylbenzene (3.3 g, 17.1 mmol) and tBuOK (25.7 mL, 1.0 M solution in tBuOH, 25.7 mmol). The reaction mixture was allowed to warm to rt and stirred for 18 h. H2O (100 mL) was added to the reaction mixture and the aqueous layer was extracted with DCM (3×100 mL). The combined organic layers were washed with sat. NaCl (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by ISCO chromatography (150 g) using hexane/EtOAc (0-5% over 30 min, 5-20% over 20 min) to give 2,2-bis(3-(trifluoromethoxy)phenyl)acetonitrile as a yellow oil at a retention time of 46 min (1.4 g, 45% yield). HPLC: RT=4.13 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.45 ppm, 2H, t, J=8.13 Hz; 7.30 ppm, 2H, d, J=7.91 Hz; 7.23 ppm, 2H, d, J=9.23 Hz; 7.17 ppm, 2H, s; 5.17 ppm, 1H, s.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.[C:13]([O-])(=O)/C=C/C([O-])=O>>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH2:8][N:9]([CH3:13])[CH2:10][CH2:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2cccnc2)s1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: Cc1cnc(C2=CCCN(C)C2)s1

Procedure:
The title compound was prepared from 88 (2.2 g, 0.013 mol) by the procedure described in Example 49. The crude free base obtained, 89, was converted to the title fumarate, 90. Yield: 0.8 g (0.0032 mol, 25%). M.P. 159°-160° C. Anal. (C12H16N2O2S) C, H, N.