Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CNC(C1SC=C(C)C=1NC1C(Cl)=CN=C(NC2C=CC3CNCC(=O)N(CC)C=3C=2)N=1)=O.[CH3:34][NH:35][C:36]([C:38]1[S:39][CH:40]=[C:41](C)[C:42]=1[NH:43][C:44]1[C:49]([Cl:50])=[CH:48][N:47]=[C:46]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[CH2:61][N:60]([CH2:62][CH3:63])[CH2:59][C:58](=[O:64])[N:57]([CH2:65][CH3:66])[C:56]=3[CH:67]=2)[N:45]=1)=[O:37]>>[CH3:34][NH:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][C:42]=1[NH:43][C:44]1[C:49]([Cl:50])=[CH:48][N:47]=[C:46]([NH:51][C:52]2[CH:53]=[CH:54][C:55]3[CH2:61][N:60]([CH2:62][CH3:63])[CH2:59][C:58](=[O:64])[N:57]([CH2:65][CH3:66])[C:56]=3[CH:67]=2)[N:45]=1)=[O:37]
Reactant: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)ccc2C1
Agent: CCN1C(=O)CNCc2ccc(Nc3ncc(Cl)c(Nc4c(C)csc4C(=O)NC)n3)cc21
Product: CCN1CC(=O)N(CC)c2cc(Nc3ncc(Cl)c(Nc4ccsc4C(=O)NC)n3)ccc2C1

Procedure:
Following a procedure analogous to Example 1856b, 3-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide was converted to 3-[5-chloro-2-(1,4-diethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-4-methyl-thiophene-2-carboxylic acid methylamide: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.62 (s, 1H), 7.3 (dd, 1H), 7.24 (s, 1H), 7.17 (d, 1H), 3.78 (q, 2H), 3.63 (s, 2H), 3.19 (s, 2H), 2.85 (s, 3H), 2.76 (q, 2H), 2.05 (s, 3H), 1.21 (t, 3H), 1.07 (t, 3H); MS (m/e): 514.5 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=O)[CH:19]=[CH:20][NH:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[CH:19][CH:20]=[N:21]2)=[CH:16][C:15]=1[O:25][CH3:26])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Yield: 21 %

Procedure:
Phosphorus oxychloride (14.19 ml) was added to 7-(benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinone (17.16 g), and the mixture was heated under reflux for one hr. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in chloroform, and the solution was made alkaline by the addition of an aqueous sodium hydroxide solution, followed by extraction with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel by development with chloroform/acetone (10/1) to give 3.82 g (yield 21%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@@H:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:27][CH3:28].[Li+].[OH-]>>[CH2:30]([O:29][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH2:27][CH3:28])[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1CC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3F)oc2C)cc1CC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{2-ethyl-4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless liquid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[OH:12]O>CCOCC>[O:12]1[C:3]2[C:4](=[O:11])[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[O:1][C:2]1=2
Reactant: O=c1ccoc2ccccc12
Reactant: OO
Solvent: CCOCC
Product: O=c1c2c(oc3ccccc13)O2
Temperature: 0 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
Chromone (3 g) was dissolved in ether (200 ml) and the solution was cooled to 0° C. in ice water. Then, 30% hydrogen peroxide (15 ml) and Triton B (10 ml) solution were added portionwise. The whole was stirred at 0° C. for 4 hours. After adding ice water, the reaction liquor was extracted with dichloromethane. The organic layer was washed with sodium thiosulfate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was fractionatedby silica gel column chromatography (diethyl ether/hexane =1:8) to give the titled compound (2.34 g; yield =75%). Melting point: 66°-67° C. Mass spectrum (M+): 162. 1H-NMR(CDCl3, δ ppm): 3.69 (d, 1H, H3), 5.67 (d, 1H, H2), 7.05 (d, 1H, H8), 7.14 (t, 1H, H6), 7.54 (t, 1H, H7), 7.79 (dd, 1H, H5).
Reaction SMILES: [CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[C:17](C(O)=O)[C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.O=O.C(=O)=O>C(OCC)(=O)C.CCCCCC>[CH2:1]1[C:8]2[N:4]([C:5]([C:9]([C:11]3[N:12]4[C:16](=[CH:17][C:18]=3[CH3:19])[CH:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:14][CH2:13]4)=[O:10])=[CH:6][CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCn2c(C(=O)c3ccc4n3CCC4)c(C)c(C(=O)O)c21
Agent: O=C=O
Agent: O=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCn2c1cc(C)c2C(=O)c1ccc2n1CCC2

Procedure:
A stirred portion (0.63 g, 0.0007 m) of the acid from Step D above in an oxygen-free atmosphere is set in an oil-bath set at 210° C. (and rising to 230° C.) and kept there until carbon dioxide evolution ceases. Chromatography of the residue obtained, using a silica gel column and 25% ethyl acetate/hexane as eluant yields pure ethyl 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-6-methyl-2,3-dihydro-1H-pyrrolizine-1-carboxylate.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:10][C:11]1[CH:24]=[C:23]2[C:14]([NH:15][C:16]3[C:21]([S:22]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=12)(=O)C.CI.C(OCC)C>CN(C=O)C.[Cl-].[Na+].O>[CH3:7][O:10][C:11]1[CH:24]=[C:23]2[C:14]([N:15]([CH3:1])[C:16]3[C:21]([S:22]2)=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=12
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Solvent: O
Product: COc1cc2c(c3ccccc13)N(C)c1ccccc1S2
Reaction time: 0.25 h

Procedure:
Potassium tert. butoxide (1.3 gm) was added to a solution of 5-acetoxy-12H-benzo[a]phenothiazine (from Example 1) (2.0 gm) and methyl iodide (4 ml) in DMF (20 ml). The reaction mixture was cooled with an ice-bath and stirred for 15 minutes. Diethyl ether (100 ml) was added to the reaction mixture followed by brine (100 ml). The ether layer was decanted, washed with brine, dried and evaporated to dryness. The resulting oily residue was chromatographed on silica gel (10% EtOAc/hexane) to afford 5-methoxy-12-methyl-12H-benzo[a]phenothiazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[C:10]1=[O:18].FC1C=CC(C2(C3C=CC(F)=CC=3)CCCN(CC(O)=O)C2=O)=CC=1.[F:44][C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[CH2:50][NH:49][CH2:48]2.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:49]2[CH2:48][C:47]3[C:51](=[CH:52][CH:53]=[C:45]([F:44])[CH:46]=3)[CH2:50]2)=[O:17])[C:10]1=[O:18]
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2Cl)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCC(c2ccc(F)cc2Cl)C1=O)N1Cc2ccc(F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(3-(2-chloro-4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid from Example 268A for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 5-fluoroisoindoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.36 (dd, J=6.0, 8.7, 1H), 7.28-7.17 (m, 1H), 7.17-7.12 (m, 1H), 7.09-6.91 (m, 3H), 4.84 (dd, J=8.5, 17.8, 4H), 4.34 (d, J=8.0, 1H), 4.24-4.07 (m, 2H), 3.77-3.56 (m, 2H), 2.76-2.55 (m, 1H), 2.03 (ddd, J=8.6, 12.8, 16.4, 1H); MS (DCI) m/z 391.1 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[C:14]3[CH2:22][NH:21][CH2:20][CH2:19][C:15]=3[N:16]=[CH:17][N:18]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)C(C)C)(C)C>>[Cl:32][C:31]1[C:26]([N:21]2[CH2:20][CH2:19][C:15]3[N:16]=[CH:17][N:18]=[C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([S:3]([C:2]([F:1])([F:23])[F:24])(=[O:4])=[O:5])=[CH:7][CH:8]=4)[C:14]=3[CH2:22]2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CNCC3)cc1)C(F)(F)F
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cc1)C(F)(F)F
Yield: 18.9 %

Procedure:
The title compound was prepared according to the procedure given for Compound 4C using 5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[4,3-d]pyrimidin-4-amine (160 mg, 0.45 mmol), 2,3-dichloropyridine (135 mg, 0.9 mmol) and N,N-diisopropylethylamine (0.16 mL, 0.9 mmol) to give the desired compound as an off-white powder (40 mg, 19%).
Reaction SMILES: [C:1](Cl)(=O)[CH:2]([CH3:4])[CH3:3].CC(C)(C)C(OC(=O)C(C)(C)C)=O.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:39]3=[CH:40][C:41]4[O:45][CH2:44][O:43][C:42]=4[CH:46]=[C:38]3[O:37][CH2:36]1)[C:24](=[O:35])[N:25]2[CH2:30][C:31](=[N:33][OH:34])[NH2:32].ON=C(N)CN1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:22]=1[C:23]1([C:39]3=[CH:40][C:41]4[O:45][CH2:44][O:43][C:42]=4[CH:46]=[C:38]3[O:37][CH2:36]1)[C:24](=[O:35])[N:25]2[CH2:30][C:31]1[N:32]=[C:1]([CH:2]([CH3:4])[CH3:3])[O:34][N:33]=1
Reactant: CC(C)C(=O)Cl
Reactant: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Cl)cccc21)=NO
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: NC(CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)=NO
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(Cl)cccc32)no1

Procedure:
Following the procedure as described in EXAMPLE 11.23 and making non-critical variations using isobutyryl chloride to replace trimethylacetic anhydride, and 2-(4′-chloro-2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)-N′-hydroxyacetimidamide to replace N′-hydroxy-2-(2′-oxo-6H-spiro[benzofuro[6,5-d][1,3]dioxole-7,3′-indoline]-1′-yl)acetimidamide, 4′-chloro-1′-{[5-(1-methylethyl)-1,2,4-oxadiazol-3-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (26%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, CDCl3) δ7.19 (dd, J=8.0, 8.0 Hz, 1H), 7.00 (dd, J=8.2, 0.8 Hz, 1H), 6.77 (dd, J=7.8, 0.7 Hz, 1H), 6.46 (s, 1H), 6.32 (s, 1H), 5.85 (ABq, 2H), 5.04 (ABq, 2H), 4.95 (ABq, 2H), 3.17 (sep, J=7.0 Hz, 1H), 1.36 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ185.2, 177.1, 165.3, 156.7, 149.2, 143.0, 142.1, 131.6, 130.1, 128.4, 124.6, 116.5, 107.3, 103.1, 101.5, 93.2, 77.1, 58.8, 36.2, 27.5, 20.1, 20.0; MS (ES+) m/z 440.1 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].S(=O)(=O)(O)[OH:18]>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1)(=[O:18])[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=S(=O)(O)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of chromium trioxide (6.5 g) in acetic anhydride (29 ml) was added dropwise to a stirred, cooled solution of 6-(4-n-propylphenyl)pyridazin-3(2H)-one (5.11 g) in acetic anhydride (25 ml) containing concentrated sulphuric acid (5 ml). The reaction mixture was stirred at room temperature for 16 hours and then poured into crushed ice (250 ml) to afford 6-(4-propionylphenyl)pyridazin-3(2H)-one (0.78 g), m.p. 202°-205° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1)(=O)=O.[Cl:31][C:32]1[CH:33]=[C:34]([OH:39])[CH:35]=[CH:36][C:37]=1[Cl:38]>CN(C=O)C>[Cl:31][C:32]1[CH:33]=[C:34]([CH:35]=[CH:36][C:37]=1[Cl:38])[O:39][C:11]1[N:12]=[C:13]([O:27][CH2:28][CH2:29][CH3:30])[C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=3)[O:17][C:15]=2[N:16]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Oc2ccc(Cl)c(Cl)c2)nc2oc(-c3cccc(C)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
103 mg of cesium carbonate and 100 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine were added to a solution of 49 mg of 3,4-dichlorophenol in 3 ml of DMF. The mixture was stirred at room temperature for 2 h. After filtration, the solvent was distilled off in vacuo, and the product was isolated via preparative HPLC to yield 54 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.N.[H][H]>O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][CH:11]([O:15][CH3:16])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: [Ni]
Agent: N
Solvent: O
Product: COC(Cc1cccc(N)c1)C(=O)O
Yield: 88.7 %

Procedure:
50 g (223 mmol) of 3-(3-nitrophenyl)-2-methoxyacrylic acid is suspended in 785 ml of water and brought into solution by the addition of 30 ml of concentrated ammonia. After addition of 3 g of Raney nickel, the mixture is hydrogenated at 80 bar until uptake of hydrogen ceases. The solution is filtered, 325 g of salt are added, and the resultant solution is thoroughly extracted with tetrahydrofuran. The combined tetrahydrofuran extracts are dried over sodium sulfate, filtered over active carbon and concentrated, thus producing 38.6 g (88% of theory) of 3-(3-aminophenyl)-2-methoxypropionic acid. This product is dissolved in 1 liter of water by the addition of 110 ml of 2N ammonia. The resultant solution is treated first with 160 ml of glacial acetic acid, and then with 36 ml of bromine in 160 ml of glacial acetic acid added dropwise at room temperature over the course of 2 hours. The reaction mixture is stirred for several hours in an ice bath, the resultant precipitate is vacuum-filtered, washed with water and dried at 50° C., thus producing 66 g (73% of theory) of 3-(3-amino-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a white powder, mp 173°-175° C. 32 g (74 mmol) of this compound is added portionwise at +5° C. to 80 ml of nitrosylsulfuric acid. Then, 40 ml of glacial acetic acid is added, and the mixture is stirred for 2 hours at +5° C. The mixture is poured onto 360 g of ice, and the resultant mixture is added to a solution of 33 g of copper(I) cyanide, 62 g of potassium cyanide and 464 ml of concentrated ammonia in 297 ml of water, resulting in discharge of gas. The reaction mixture is stirred overnight at room temperature, treated with 1 liter of ethyl acetate, and brought to pH 2 by addition of concentrated hydrochloric acid. After pressure filtration, the ethyl acetate phase is separated and the aqueous phase is again thoroughly extracted with ehtyl acetate. The combined ethyl acetate extracts are drid over sodium sulfate, filtered over active carbon and vacuum-concentrated to dryness, thus producing 24 g of crude 3-(3-cyano-2,4,6-tribromophenyl)-2-methoxypropionic acid. This product is hydrolyzed to the amide by stirring at 60° C. in 100 ml of water containing 3 g of caustic soda for 3 hours. The resultant solution is filtered over active carbon and the filtrate is brought to pH 2 with concentrated hydrochloric acid. The resultant mixture containing a precipitate is stirred for several hours in an ice bath, vacuum-filtered, washed with water and dried at 50° C., thus producing 27.5 g (81% of theory) of 3-(3-carbamoyl-2,4,6-tribromophenyl)-2-methoxypropionic acid, as a white powder, mp 138°-139° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:51])[C@H:3]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:4](=[O:45])[N:5]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][NH:41]7)=[N:37][CH:36]=6)[CH:31]=5)[CH:26]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6]1.[CH3:52][O:53][C:54]([NH:56][C@H:57]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:58](O)=[O:59])=[O:55].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C)C=O>[CH3:49][O:48][C:47](=[O:50])[NH:46][C@@H:3]([CH:2]([CH3:51])[CH3:1])[C:4]([N:5]1[C@H:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:39][C:38]([C@@H:40]7[CH2:44][CH2:43][CH2:42][N:41]7[C:58](=[O:59])[C@H:57]([NH:56][C:54]([O:53][CH3:52])=[O:55])[C:61]7[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=7)=[N:37][CH:36]=6)[CH:31]=5)[CH:26]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH2:12][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:6]1)=[O:45]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C

Procedure:
Methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate as 3HCl salt (200 mg, 0.24 mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (60 mg, 0.288 mmol), and COMU (154 mg, 0.36 mmol) were all weighed out in a scintillation vial and anhydrous N,N-dimethylformamide (2.4 mL) was added and without stirring to this mixture was then added DIPEA (124 mg, 0.96 mmol) and the mixture was sonicated to dissolve all the reactants as quickly as possible. The mixture was then stirred for 2 h at room temperature. The crude mixture was diluted with EtOAc and washed with brine, 10% Na2CO3, brine and the organic layer was dried over MgSO4. The filtrate was concentrated down and the residue was purified by normal phase column chromatography (5% MeOH/DCM). MS (ESI) m/z 881.84 [M+H]+. (95 mg, 45%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])[C:2]#[CH:3].[CH:13]([Mg]Br)=[CH2:14].[NH4+].[Cl-]>C1COCC1>[CH2:1]([S:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]([OH:8])[CH:13]=[CH2:14])[C:2]#[CH:3]
Reactant: C=C[Mg]Br
Reactant: C#CCSc1ccccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCSc1ccccc1C(O)C=C
Temperature: 25 °C

Procedure:
To 35.2 g of 2-(2-propynylthio)benzaldehyde in dry THF cooled to between -60° and -70° C. was added 210 ml of a 1M solution of vinylmagnesium bromide solution dropwise at -60° C. and the reaction mixture allowed to warm to room temperature. The reaction mixture was poured into saturated NH4Cl and extracted twice with diethyl ether. The extracts are washed with water and then brine and dried over MgSO4 to afford 42.1 g of the subtitle compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:33])(=[O:32])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:16][CH:15]=2)[C:9](=[O:12])[NH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].[CH:34](I)([CH3:36])[CH3:35].O>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26](=[O:32])(=[O:33])[NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:19]=2)[C:9](=[O:12])[N:10]([CH:34]([CH3:36])[CH3:35])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn(C(C)C)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a suspension of 54 mg (1.35 mmole) of sodium hydride (60% in oil) in 1 ml of dry DMF was added 200 mg (0.452 mmole) of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G). The resulting mixture was stirred under N2 at room temperature for 2 hours. Then 270 μL (460 mg, 2.70 mmole) of isopropyl iodide was added dropwise, and the orange mixture was stirred at room temperature overnight. Next, the mixture was treated with H2O and extracted 4× with ethyl acetate. The combined organic fractions were washed with brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo, and the residue was flash chromatographed twice on silica gel (elution with 1.5% MeOH in CH2Cl2) to yield 106 mg (48%) of the title compound; satisfactory purity by TLC in 98.5:1.5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 485 (M+1)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:15]1([CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[OH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:15]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1
Reactant: ClCCCCCCOC1CCCCO1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 10 g of 2-(6-chlorohexyloxy)tetrahydropyrane, 25 g of hydroquinone, 31 g of potassiumcarbonate, 0.752 g of potassiumiodide and 250 ml of dimethylsulfoxide was allowed to react for 4 days at 80° C. Subsequently, the reaction mixture was cooled to room temperature and after addition of water extracted with ether. The organic phase was then dried over sodium sulphate, filtered and concentrated to dryness. Chromatography on silica with 10% ethylacetate in toluene gave 11 g of product as a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[CH3:18]C(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>C1COCC1>[F:16][C:13]([F:14])([F:15])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1)([O:17][CH3:18])[C:9]([F:10])([F:11])[F:12]
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 2-(4-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1 eq.), DIAD (1.96 eq.), PPh3 (polymer-bound, 2.36 eq) and MeOH (1.1 eq) in THF (100 mL) was stirred at reflux for 16 h. After filtration and concentration, the crude was purified by flash chromatography (20% EtOAc/CH2Cl2) to give the title compound as a white solid. MS (ES+): 274 (M+H)+. Calc'd for C10H9F6NO—273.06.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[Cl:23])[NH2:19].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:16]([Cl:15])[CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ccc(NC2CCN(Cc3ccccc3)CC2)cc1Cl
Reaction time: 48 h

Procedure:
190 mmol of 1-benzyl-4-piperidone, 240 mmol of 3,4-dichloroaniline, 0.02 g of PTSA and 200 ml of toluene are placed in a round-bottomed flask equipped with a reflux condenser and a Dean and Stark apparatus. The whole mixture is brought to reflux for 24 hours. After evaporation of the solvent, the residue is taken up in 500 ml of methanol and 450 mmol of sodium borohydride are progressively added. The whole mixture is kept stirring for two days. The expected product is obtained after concentration by filtration of the precipitate formed.