Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[C:12]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:24])=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[O+][O-].Br[CH2:35][C:36]([O:38][CH3:39])=[O:37]>CC(C)=O>[CH3:39][O:38][C:36](=[O:37])[CH2:35][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[C:10]([CH3:24])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]3[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1
Reactant: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(O)cc3)c12
Reactant: COC(=O)CBr
Agent: O=[O+][O-]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenol (0.260 g, 0.668 mmol) was reacted with K2C(O3 (0.120 g, 0.868 mmol) and methyl bromoacetate (0.133 g, 0.868 mmol) in acetone (5 ml) to give the product (0.271 g, 0.587 mmol, 88%) as a viscous oil. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 3.71 (s, 3H), 4.84 (s, 2H), 5.29 (s, 2H), 6.84 (d, J=7.0 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.11 (t, J=7.3 Hz, 1H), 7.16 (t, J=7.2 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.31-7.35 (m, 5H), 7.41 (t, J=7.2 Hz, 1H), 7.45 (t, J=7.5 Hz, 2H); [ESI(+)], m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:34][CH2:33][CH2:32][C@H:24]4C(OC(C)(C)C)=O)=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:34][CH2:33][CH2:32][CH2:24]4)=[CH:19][CH:18]=3)[CH2:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1c1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC1CN(c2ccc(N3CCCC3)cc2)C(=O)O1)c1ccc(Cl)s1

Procedure:
780 mg (1.54 mmol) of tert-butyl 1-{4-[5-({[(5-chloro-2-thienyl)carbonyl]amino}-methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}prolinate are dissolved in 6 ml of dichloromethane and 9 ml of trifluoroacetic acid, and the mixture is stirred at 40° C. for two days. The reaction mixture is then concentrated and stirred with ether and 2N aqueous sodium hydroxide solution. The aqueous phase is concentrated and stirred with ether and 2N hydrochloric acid. The organic phase of this extraction is dried over MgSO4, filtered and concentrated. The crude product is chromatographed over silica gel (CH2Cl2/EtOH/conc. aqu. NH3 sol.=100/1/0.1 to 20/1/0.1). This gives 280 mg (40% of theory) of the product.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH3:22])\[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(O)(=O)C>[C:1]([O:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]/[N:12]=[C:13](/[C:21](=[O:23])[CH2:22][Cl:27])\[C:14]([OH:16])=[O:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@H](O/N=C(/C(C)=O)C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@@H](O/N=C(\C(=O)O)C(=O)CCl)CC1

Procedure:
tert-Butyl (Z)-2-(cis-4-Acetoxycyclohexyloxyimino)-3-oxobutyrate (327 mg, 1 mmol), as prepared in Example 61a, was reacted with sulphuryl chloride (0.8 ml) in glacial acetic acid (2 ml) as described in Example 57d to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=O)=[CH:12][CH:11]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:39]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH2:41][CH2:40]1.C1CCN2C(=NCCC2)CC1.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([NH:45][S:42]([CH:39]2[CH2:41][CH2:40]2)(=[O:44])=[O:43])=[O:23])=[CH:14][CH:15]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NS(=O)(=O)C1CC1)c1cccc(COc2ccc(-c3cc(F)c(F)cc3F)cc2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 40.1 %

Procedure:
A solution of 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoic acid (5.0 g, 13.96 mmol) in THF (100 mL) was treated with CDI (3.37 g, 20.78 mmol), heated at 50° C. for 30 min, cooled to room temperature, added cyclopropanesulfonamide (1.86 g, 15.35 mmol) and DBU (4.2 mL, 28.08 mmol) and heated at 60° C. for 17 h. The reaction mixture was cooled to room temperature, treated with aqueous 2N HCl (50 mL), stirred for 10 min, added water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, washed with conc. HCl (20 mL), water (50 mL), 1/1 water/brine (50 mL), brine (50 mL), dried (MgSO4), filtered, concentrated and recrystallized from methanol to give cyclopropanesulfonic acid 3-(2′,4′,5′-trifluoro-biphenyl-4-yloxymethyl)-benzoylamide (2.58 g, 40.1%) as a white solid. LC-MS (ES) calculated for C23F18F3NO4S, 461.46; found m/z 460 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: Clc1ccc2c(N3CCNCC3)n[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OCCCN1CCN(c2n[nH]c3cc(Cl)ccc23)CC1
Reaction time: 40 h
Yield: 111.3 %

Procedure:
A mixture of 6-chloro-3-(1-piperazinyl)-1H-indazole (3.4 g, 14 mmol), K2CO3 (2.5 g, 18 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol), KI (200 mg), and acetonitrile (125 ml) was stirred at reflux under N2 for 30 hours. After standing at room temperature for 40 hours, the reaction was filtered and the filter cake was washed well with acetonitrile. The filtrate was concentrated to an oily solid, which was partitioned between water and ethyl acetate. The ethyl acetate extract was washed with water, dried with MgSO4, and concentrated to yield 6.9 g of a dark oil, which solidified after 2 days under vacuum. The product was purified by preparative HPLC (Waters Associates Prep LC/system 500 utilizing 2 silica gel columns and 6% methanol/methylene chloride as eluent) to yield 4.2 g. The material was recrystallized from ethanol to yield 3.4 g of glistening, beige, 1-[4-[3-[4-(6-chloro-1H-indazol-3-yl)-1-piperazinyl]propoxy]-3-methoxy-]-ethanone crystals, m.p.=132°-134° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[CH:31]1[C:39]2[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[O:36][C:35]=2[C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:30])[C@@H:4]1[CH2:8][CH:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:43]4[C:37]5[O:36][C:35]6[CH:34]=[CH:33][CH:32]=[CH:31][C:39]=6[C:38]=5[CH:40]=[CH:41][CH:42]=4)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:6][N:5]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(Br)cc3)cc2)CN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(Oc2ccc(-c3ccc(-c4cccc5c4oc4ccccc45)cc3)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 4-(4′-bromobiphen-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (476 mg, 1 mmol), 4-dibenzofuranylboronic acid (222 mg, 1.05 mmol) and Pd(PPh3)4 (52 mg, 5% mol) in toluene (10 mL) and ethanol (2.5 mL) was heated until the solution became clear and subsequently treated with 2 M K2CO3 (1.5 mL). The reaction mixture was heated to reflux for 2 h, cooled to room temperature, diluted with ethyl acetate (100 mL). The organic layer was washed successively with 2% aq HCl and sat. aq NaCl, dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (2-10% ethyl acetate in heptane) gave 4-(4′-dibenzofuran-4-yl-bipheny-4-yloxy)-N-tert-butoxycarbonyl-proline methyl ester (423 mg, 75%) as a foam. 1H NMR (CDCl3), δ 7.97 (m, 4H), 7.71 (dd, J=1, 8 Hz, 2H), 7.62 (m, 4H), 7.45 (m, 3H), 6.90 (dd, J=1, 9 Hz, 2H), 4.96 (m, 1H), 4.52 (m, 1H), 3.78 (m, 5H), 2.52 (m, 2H), 1.46 (s, 9H). LCMS 464 (M+−100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].P([O-])([O-])(O)=O.[Na+].[Na+].[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20].NC1C=CC=CC=1>O.O1CCOCC1>[C:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:31])=[O:30])=[CH:25][CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Nc1ccccc1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)O)cc1
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
2-Amino-5-chlorobenzoic acid (200 g, 1.17 mol) was added to a solution of sodium hydrogen phosphate (497 g, 3.50 mol) in water (2.4 L) at 70° C. and was stirred until homogeneous (˜10 min). 4-tert-Butylbenzenesulfonyl chloride (353 g, 1.52 mol), dissolved in 800 mL p-dioxane, was added to the stirring aniline solution in a steady stream over a ½ hour period via a 1 liter addition funnel. The resultant mixture was stirred at 70° C. overnight. The following day, upon LCMS verification of consumption of the aniline, the reaction mixture was divided into two equal portions for ease of handling. Each portion was poured in a slow stream into two liters of rapidly stirring 2 M HCl/H2O in a four liter Erlenmeyer flask. The resultant precipitate was collected by vacuum filtration and washed well with water. The precipitate from each portion were subsequently combined and dried in vacuo to afford 320 g 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-benzoic acid as an off-white solid (87% yield): HPLC retention time=2.76 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., using a 1 mL/min flow rate, a 2.5 minute gradient of 20-100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.08% formic acid/5% water/94.9% acetonitrile)); MS (ES) M+H expected 368.0, found 368.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]1[O:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:18][N:19]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:20]1([C:17]2[O:16][C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[N:19][N:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1Cc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2nnc(CC3CCCCN3)o2)cc1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of (RS)-2-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-piperidine-1-carboxylic acid tert butyl ester (0.175 g) in dichloromethane (4 ml) was cooled (ice bath) and treated with trifluoroacetic acid (1 ml). The mixture was stirred for 1 h, added to saturated potassium carbonate and the product extracted into dichloromethane. The organic phase was dried (MgSO4) and solvent removed at reduced pressure to give the title compound (0.115 g)
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[O:7])[CH2:3][CH2:2]1.[Cl-].[NH4+].C(O)C.CN(C)C=O>[Fe].O>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH:13]=2)=[CH:16][CH:17]=1
Reactant: O=C(NCC1CC1)c1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc(C(=O)NCC3CC3)c2)cc1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
After adding 0.35 g of 2-[(cyclopropylmethyl)aminocarbonyl]-4-(4-nitrophenoxy)pyridine to a mixture of 0.7 g of iron powder, 1.4 g of ammonium chloride, 10 ml of ethanol, 10 ml of dimethylformamide and 5 ml of water, the mixture was vigorously stirred at 100° C. for 20 minutes. The reaction solution was filtered with celite and the solvent was distilled off under reduced pressure to obtain 0.37 g of the target substance as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19]COC)=[CH:15][CH:14]=3)=[CH:11][S:10][C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([O:28][CH3:29])[CH:3]=1.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)=[CH:11][S:10][C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[C:4]([O:28][CH3:29])[CH:3]=1
Reactant: COCOc1ccc(-c2csc(CCC(=O)O)c2-c2ccc(Cl)cc2OC)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1-c1c(-c2ccc(O)cc2)csc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.8 %

Procedure:
To a solution of 3-(3-(4-chloro-2-methoxyphenyl)-4-(4-(methoxymethoxy)phenyl)thiophen-2-yl)propanoic acid (190 mg, 0.44 mmol) in THF (5 mL) was added HCl (1 mL, 12 M) and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc, and concentrated to give the crude compound, which was purified by preparative HPLC (Column: YMC ODS-AQ 150×30 cm, 5 μm; Retention Time: 15 min; Mobile phase: from 38% MeCN in water (0.05% TFA) to 68% MeCN in water (0.05% TFA); Wavelength: 220 nm, 254 nm; sample dissolved in DMSO) to give 3-(3-(4-chloro-2-methoxyphenyl)-4-(4-hydroxyphenyl)thiophen-2-yl)propanoic acid (47.5 mg, yield 28%). 1H NMR (CD3OD 400 MHz): δ 7.11 (s, 1H), 6.99 (d, J=1.6 Hz, 1H), 6.97-6.92 (m, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.58 (d, J=8.8 Hz, 2H), 3.58 (s, 3H), 2.90 (t, J=8.0 Hz, 2H), 2.50 (t, J=8.0 Hz, 2H); MS (ESI): m/z [M+1]+=389.1.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([CH3:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([O:17][C:16]([F:15])([F:26])[F:27])=[CH:19][CH:20]=1)[CH2:12]2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(C)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
A mixture of 4-bromo-2-bromomethyl-6-methyl-benzoic acid methyl ester (1.61 g, 5.0 mmol), 4-trifluoromethoxy-benzylamine (0.916 mL, 6.0 mmol), and K2CO3 (1.24 g, 9.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-bromo-7-methyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (1.21 g, 60%). GC-MS: m/z 399 (M)+, 316 (M−83)+.
Reaction SMILES: [O:1]1[C:5]2C=CC=C[C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[NH:35][C:36](=[O:40])[CH2:37][O:38][CH3:39])[CH2:24][CH:23]2[OH:41])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[NH:35][C:36](=[O:40])[CH2:37][O:38][CH3:39])[CH2:24][C:23]2=[O:41])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: COCC(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCC(=O)Nc1cc(F)ccc1N1CCC(NC(=O)C2(NC(=O)c3ccco3)CCCCC2)C(=O)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 82.1 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(4-fluoro-2-methoxyacetylaminophenyl)piperidin-3-ol (1.1 g) obtained in Step 3 in 5 ml of dimethyl sulfoxide, was added dropwise 1.2 ml of triethylamine. The reaction mixture was cooled to 0° C. Pyridine-SO3 complex (0.9 g) was added to the reaction mixture, which was then stirred for about 4 hours at room temperature. The reaction mixture was diluted with 20 ml of ethyl acetate and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 820 mg of the titled compound.
Reaction SMILES: [CH2:1]([C:8]1[N:16]2[C:11]([C:12]([NH:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:23](=[O:27])[C:24]([NH2:26])=[O:25])[C:9]=1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1N2C(C(NCC(O)=O)=CC=C2)=C(C(=O)C(N)=O)C=1C)C1C=CC=CC=1.CO>CCOCC>[CH3:22][O:21][C:19]([CH2:18][NH:17][C:12]1[C:11]2[N:16]([C:8]([CH2:1][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:9]([CH3:28])[C:10]=2[C:23](=[O:27])[C:24]([NH2:26])=[O:25])[CH:15]=[CH:14][CH:13]=1)=[O:20]
Reactant: COC(=O)CNc1cccn2c(Cc3ccccc3)c(C)c(C(=O)C(N)=O)c12
Agent: Cc1c(C(=O)C(N)=O)c2c(NCC(=O)O)cccn2c1Cc1ccccc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)CNc1cccn2c(CC3CCCCC3)c(C)c(C(=O)C(N)=O)c12

Procedure:
Compound 89a was converted to 90a by the same procedure cited for the preparation of 52 from 51. Mp, 293° C. (dec.) (methanol:ether). 61% Yield.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]3[CH2:18][CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:21]=[C:12]23)[CH:8]=[CH:7][N:6]=1)(=O)=O.[NH2:28][CH:29]([CH3:39])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=1.O1CCOCC1>CN1CCCC1=O>[OH:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:29]([NH:28][C:5]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][C:14](=[O:17])[N:13]4[CH2:18][CH:19]=[C:20]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:21]=[C:12]34)[CH:8]=[CH:7][N:6]=2)[CH3:39])=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)c1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Reactant: CC(N)Cc1ccc(CO)cc1
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1

Procedure:
1-(2-methanesulfonyl-pyrimidin-4-yl)-8-phenyl-1,2,3,6-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (1.1 g, 2.9 mmol) and [4-(2-amino-propyl)-phenyl]-methanol (0.96 g, 5.8 mmol) in 1:1 dioxane: 1-methyl-2-pyrrolidinone (16 mL) was heated to 100° C. for 20 h. The mixture was partitioned between water (30 mL) and ethyl acetate (60 mL). The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-8% 2M NH3 MeOH/CH2Cl2 to afford a white solid. M+1=469. 1NMR (CDCl3) d (3H, 1.21 ppm), s (1H, 1.79 ppm), m (2H, 2.22 ppm), m(1H, 2.79 ppm), m (1H, 2.98 ppm), m (4H, 4.11 ppm), m (1H, 4.13 ppm), b(3H, 4.68 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.29 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).
Reaction SMILES: CO[C:3]1C=C[C:11]([CH:14]=[O:15])=[CH:10][C:4]=1[C:5](=[N:8]O)OC.S(Cl)(Cl)=O.[C:20]([O:23][CH2:24]C)(=[O:22])[CH3:21].[CH3:26]CCCCC>ClCCl>[CH3:26][O:15][C:14]1[CH:11]=[CH:10][C:4]([C:5]#[N:8])=[CH:3][C:21]=1[C:20]([O:23][CH3:24])=[O:22]
Reactant: CCOC(C)=O
Reactant: COC(=NO)c1cc(C=O)ccc1OC
Reactant: CCCCCC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C#N)ccc1OC
Reaction time: 0.33 h

Procedure:
Combine methyl 2-methoxy-5-formylbenzoate oxime (3.5 g, 16.7 mmol) in dichloromethane (75 mL) and cool in an ice-bath. Add dropwise thionyl chloride (2.0 mL, 27.2 mmol). after 20 minutes, dilute the reaction mixture with dichloromethane and extract with a saturated aqueous solution of sodium bicarbonate and then brine. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give methyl 2-methoxy-5-cyanobenzoate.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@H:12]1[N:16]2[C:17](=[O:31])[C@@H:18]([NH:23][C:24](=[O:30])[C@@H:25]([N:27](C)[CH3:28])[CH3:26])[CH2:19][CH:20]=[CH:21][CH2:22][C@H:15]2[CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(C)C=CC=CC=1>ClCCl>[CH2:1]([NH:9][C:10]([C@H:12]1[N:16]2[C:17](=[O:31])[C@@H:18]([NH:23][C:24](=[O:30])[C@@H:25]([NH:27][CH3:28])[CH3:26])[CH2:19][CH:20]=[CH:21][CH2:22][C@H:15]2[CH2:14][CH2:13]1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](C(=O)N[C@H]1CC=CC[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O)N(C)C
Agent: CN[C@@H](C)C(=O)N[C@H]1C/C=C\C[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O
Agent: C[C@@H](C(=O)N[C@H]1C/C=C\C[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O)N(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H]1CC=CC[C@H]2CC[C@@H](C(=O)NCCc3ccccc3)N2C1=O

Procedure:
Product 11I is reconstituted in 20% trifluoroacetatic acid in dichloromethane (50 mL). Stirring until reaction complete by HPLC. Toluene is added and concentrated to an amber oil. The product is dissolved in dichloromethane and washed with saturated bicarb followed by drying over anhydrous magnesium sulfate, filtering and concentrating. HPLC purification to yield 12. LCMS characterization ES+413.1 (m+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH2:19])[C:7]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[C:27](Cl)(=[O:29])[CH3:28]>O.ClCCl>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:8]([CH2:17][CH2:18][NH:19][C:27](=[O:29])[CH3:28])[C:7]=2[CH:20]=1
Reactant: NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Reactant: CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound obtained in Step E is dissolved in a mixture of water/dichloromethane (2/3); 2 eq. of potassium carbonate are then added and 2 eq. acetyl chloride are added dropwise. After stirring for 2 hours at ambient temperature, the 2 phases are separated; the organic phase is washed with 1M HCl and then with water, until the washing waters are neutral, and is then dried over MgSO4 and evaporated. The residue obtained is purified by chromatography on silica gel.