Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][C:4]=2[N:5]=[C:6]([CH2:8][O:9][CH2:10][CH:11]([CH3:13])[CH3:12])[N:7]=1.Cl.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:10]([O:9][CH2:8][C:6]1[N:7]=[C:2]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][N:31]=2)[C:3]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][C:4]=2[N:5]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)COCc1nc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Heat a mixture of 4-chloro-2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine (79.2 mg, 0.2 mmol), 2-amino-5-trifluoromethylpyridine hydrochloride (39.6 mg, 0.2 mmol), xantphos (11.6 mg, 0.1 mmol), Pd2(dba)3 (18.3 mg, 0.1 mmol) and Cs2CO3 (130 mg, 0.4 mmol) in dioxane (2.0 mL) at 100° C. for 20 hours. Cool the mixture, concentrate under vacuum, dilute with water (5.0 mL), extract with EtOAc (3×3 mL) and dry with MgSO4. Filter the dried extract and concentrate under vacuum to afford crude product. Purify by flash column chromatography to afford title compound as a yellow solid. 1H NMR (400 MHZ, DMSO-D6) d 0.88 (6H, d, J=1.7), 1.89 (1H, m), 3.37 (2H, d, J=1.6), 4.67 (2H, s), 7.79 (1H, m), 7.96(1H, d, J=2.1), 8.19 (1H, d, J=1.7), 8.42 (1H, d, J=2.0), 8.82(2H, m), 8.98(1H, d, J=1.1), 9.34 (1H, d, J=2.1). MS=523.2 (M+H). IC50 in standard assay of capsaicin receptor activity is less than 10 nanomolar.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])(=O)C.N>[Zn].CO>[CH2:22]([CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])=[O:8])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Agent: [Zn]
Solvent: CO
Product: C[C@H](NC(=O)C(CS)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
Treat the product from Step 1 with methanol saturated with ammonia as described in Example 12, Step 3 (before chromatography). Treat the resultant residue with zinc powder as described in Example 17. Chromatograph the product on flash grade silica gel using CH2Cl2MeOH:NH40H (97.5:2.5:0.25) to give the title compound, [α]D26 =-118.2° (MeOH).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[S:10](=[O:13])(=[O:12])[NH2:11])[NH2:6].[Cl:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:16][CH2:17][C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([S:10](=[O:12])(=[O:13])[NH2:11])=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=1)=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(S(N)(=O)=O)c(C(F)(F)F)c1
Product: NS(=O)(=O)c1ccc(NC(=O)CCl)cc1C(F)(F)F

Procedure:
3-Trifluoromethyl-4-sulphamoylaniline (24.0g) and α-chloroacetyl chloride (20 ml) were refluxed together 30 mins and the mixture worked up as in Example 2(a) to yield 28 g, m.p. 185°-190°
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=2[C:9]2[N:14]=[C:13]([N:15]3[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]3)[CH:12]=[CH:11][CH:10]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3O)n2)c1C(F)(F)F
Reactant: BrCc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OCc3ccc(Br)cc3)n2)c1C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a vial containing the title compound from Example 12 Step B (320 mg, 0.82 mmol) were added 4-bromobenzyl bromide (245 mg, 0.98 mmol), cesium carbonate (533 mg, 1.64 mmol), and DMF (3 mL), and the resulting mixture was stirred at 45° C. After 1 h, the reaction mixture was allowed to cool to ambient temperature, then was loaded directly onto a silica gel column and purified (0 to 30% EtOAc in hexanes, then 30% EtOAc in hexanes) to provide the title compound: LCMS m/z 562.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.77 (d, J=3.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 7.16 (dd, J=8.0, 3.0 Hz, 1H), 6.92 (d, J=8.5 Hz, 1H), 5.06 (s, 2H), 4.39 (q, J=7.0 Hz, 2H), 2.35 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[NH:18])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:2].C([Li])CCC.Cl[P:25]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[N:18][P:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCc1ccccc1NC(=N)c1ccc(C)cc1
Agent: [Li]CCCC
Product: CCc1ccccc1NC(=NP(c1ccccc1)c1ccccc1)c1ccc(C)cc1

Procedure:
Procedure as described for NP Amidine I using the following amounts: 1.19 g of N1-(2-ethylphenyl)-4-methylbenzamidine (Amidine VIII, 5.0 mmol), 2.50 mL of 2.0 M butyllithium (5.0 mmol), 0.93 mL chlorodiphenylphosphine (5.0 mmol). After filtration to remove lithium chloride and removal of solvent, the residue was treated with 20 mL of pentane. The light yellow solid was collected and dried (1.45 g, 69%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])=[CH:4][CH:3]=1.[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].CCN(CC)CC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:9][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH:3][CH:4]=1
Reactant: NC(c1ccccc1)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To 2-b′ (9 g, 25 mmol), diethyl phosphite (10.5 g, 75 mmol) and Et3N (8.5 g, 75 mmol) in toluene was added PdCl2(dppf) (7.5 g). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with saturated NH3Cl. The organic layer was concentrated under vacuum and the residue was purified over silica gel to provide the crude product 2-c (15 g). (M+Na)+=442.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])=[CH:4][CH:3]=1.C(OO)(=[O:15])C.C([O-])(=O)C.[Na+].O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OO
Reactant: C=CCCCc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(CCCC2CO2)cc1

Procedure:
To a solution of 5-(4-chlorophenyl)pent-1-ene (43.2 g) in dichloromethane (400 mL) was added dropwise with stirring a mixture of 40% peracetic acid (200 mL) and sodium acetate (6.5 g). The resulting mixture was heated under reflux for 2 hours, cooled, and stirred with water (400 mL). The dichloromethane layer was separated, washed with dilute aqueous potassium carbonate until neutral, water, and dried (MgSO4) and evaporated to give 46.7 g of 5-(4-chlorophenyl)-1,2-epoxypentane as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].Cl>O1CCOCC1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:21])[CH:19]=[CH2:20])=[CH:3][CH:4]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-aminobenzenesulfonamide (1.00 g) and pyridine (1.41 mL) were added to 1,4-dioxane (30 mL). Acryloyl chloride (0.49 mL) was added dropwise and the solution was stirred for 3 hours at room temperature. 1M HCl was added, and the solution extracted with ethyl acetate. The extracts were dried using brine and anhydrous sodium sulfate and the solvent was removed to afford crude product of sufficient purity for subsequent use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH:9]([OH:20])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:11].ClC1C=C(F)C=CC=1C(O)C(O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([OH:20])[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[O:11]
Reactant: O=C(Nc1ccc(Cl)cc1)C(O)c1ccc(F)cc1Cl
Agent: O=C(O)C(O)c1ccc(F)cc1Cl
Product: O=C(Nc1ccc(Cl)cc1)C(O)c1ccccc1Cl

Procedure:
In the same way, (2-chloro-4-fluorophenyl)-N-(4-chlorophenyl)hydroxyacetamide, compound VII.3, is prepared from (2-chloro-4-fluorophenyl)hydroxyacetic acid (synthesized according to J. Med. Chem., 1987, 30 (8), 1447, from 2-chloro-4-fluorobenzaldehyde and bromoform); M.p.=136° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cccc(Cl)c1F
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccc(Cl)c1F
Temperature: 120 °C
Yield: 43.1 %

Procedure:
1-(3-Chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (22 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 8.37 (m, 1H), 8.16 (m, 1H), 7.87 (d, 1H, J=7.2 Hz), 7.65 (m, 1H), 7.41 (m, 1H), 7.10 (t, 1H, J=8.0 Hz), 3.71 (m, 4H), 2.95 (m, 4H), 2.38 (s, 3H). ESI-MS: 440.1 [M+H]+.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH2:35][CH3:36])[Si:5]1(N(CC)CC)[C:9]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]1[Si:26]([CH3:29])([CH3:28])[CH3:27])[CH3:3]>CCOCC>[Cl:1][Si:5]1([N:4]([CH2:35][CH3:36])[CH2:2][CH3:3])[C:9]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]1[Si:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: Cl
Reactant: CCN(CC)[Si]1(N(CC)CC)C([Si](C)(C)C)=C(c2ccccc2)C(c2ccccc2)=C1[Si](C)(C)C
Solvent: CCOCC
Product: CCN(CC)[Si]1(Cl)C([Si](C)(C)C)=C(c2ccccc2)C(c2ccccc2)=C1[Si](C)(C)C
Reaction time: 20 h
Yield: 78 %

Procedure:
Dry hydrogen chloride gas was blown into a 100 ml ether solution of 4.17 g of 1,1-bis(diethylamino)-3,4-diphenyl-2,5-bis(trimethylsilyl)silole at -78° C. for one hour. After distilling ether off, dichloromethane was added, and then 1.3 ml of triethylamine and 1 ml of diethylamine were added in order. After continuing stirring at room temperatures for 20 hours, the solvent was distilled off, and dry hexane was added to remove insoluble matters by filtering. Then, hexane was distilled off from the filtrate to obtain a product. This product was refined by distillation to obtain 3.0 g of 1-chloro-1-diethylamino-3,4-diphenyl-2,5-bis(trimethylsilyl)silole. The yield was 78%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].[H][H]>CO.[Pd].C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:2]
Reactant: CCOC(=O)C(=CCCc1ccccc1)CCCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(CCCc1ccccc1)CCCc1ccccc1
Yield: 98 %

Procedure:
A solution of ethyl-2-(3-phenylpropyl)-5-phenyl-2-pentenoate in methanol (10 mL) was added to a suspension of 10% palladium on carbon (0.112 g) in methylene chloride (10 mL) and the mixture was hydrogenated under 60 psi of hydrogen for 6 h. The catalyst was removed by filtration through a pad of celite and the solvent was removed under reduced pressure to give ethyl-2-(3-phenylpropyl)-5-phenyl-pentanoate (0.787 g, 98%). The crude product was not purified further but used directly in the next step. 1H NMR (300 MHz, CDCl3): δ 1.25 (t, 3 H, J=7.1), 1.60 (m, 8 H), 2.39 (m, 1 H), 2.61 (t, 4 H, J=7.3), 4.14 (q, 2 H, J=7.1), 7.24 (m, 10 H).
Reaction SMILES: [C:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][S:10]1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Cl:15]N1C(=O)CCC1=O.C1(=O)NC(=O)CC1>C(Cl)(Cl)Cl>[Cl:15][C:12]1[C:13](=[O:14])[N:9]([C:1]([CH2:4][C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:2])[CH3:3])[S:10][CH:11]=1
Reactant: CC(C)(C)CC(C)(C)n1sccc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C1CCC(=O)N1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)CC(C)(C)n1scc(Cl)c1=O
Reaction time: 2.5 h

Procedure:
To a solution of 10.7 g. (0.05 mole) of 2-t-octyl-3-isothiazolone in 100 ml. of chloroform is added in a single portion 13.3 g. (0.1 mole) of N-chlorosuccinimide. The mixture warms somewhat but does not require cooling. After stirring for 2.5 hours, the mixture is filtered giving 7.5 g. of crude succinimide. The filtrate is evaporated under reduced pressure and the residue dissolved in ether. The ether solution is extracted with water, dried over anhydrous magnesium sulfate, and evaporated to a mixture of solid and oil. The oil is washed from the solid with hexane leaving 1.7 g. (14%) of white 4-chloro-2-t-octyl-3-isothiazolone, m.p. 137°-140°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH2:6])[CH3:5].Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([C:20]3[C:21]([CH3:26])=[N:22][O:23][C:24]=3[CH3:25])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>CN1C(=O)CCC1.O>[CH3:26][C:21]1[C:20]([C:14]2[CH:13]=[C:12]3[C:17]([C:8]([NH:6][CH:4]([CH3:5])[CH2:3][O:2][CH3:1])=[C:9]([N+:27]([O-:29])=[O:28])[CH:10]=[N:11]3)=[CH:16][C:15]=2[O:18][CH3:19])=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: COCC(C)N
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: COCC(C)Nc1c([N+](=O)[O-])cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
1-(Methyloxy)-2-propanamine (0.35 g) and 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 8) (0.74 g, 2.217 mmol) were dissolved in a mixture of triethylamine (0.30 ml, 2.2 mmol) and NMP (3 ml) and the solution was allowed to stand for 30 min at room temperature, then diluted with water (20 ml) and the resulting suspension stirred for 20 min, then filtered and the resulting solid washed with water (10 ml) and dried in the vacuum oven at 50° C. to give the title compound as bright yellow solid. (0.80 g, 2.070 mmol, 93% yield). LCMS (formate) Rt 0.97 MH+ 387
Reaction SMILES: C([C@H]1COC(C)(C)N1C(=O)CC1C=CN(C2C=CC(C3C=CC=CC=3)=CC=2)C=1)C1C=CC=CC=1.[CH2:35]([O:37][C:38](=[O:61])[CH:39](OC(=O)C)[C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]>>[CH2:35]([O:37][C:38](=[O:61])[CH2:39][C:40]1[O:44][C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)=[CH:42][CH:41]=1)[CH3:36]
Reactant: CCOC(=O)C(OC(C)=O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)Cc1ccn(-c2ccc(-c3ccccc3)cc2)c1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Yield: 61 %

Procedure:
According to the procedure described in Example 13 for the preparation of (4(S)-benzyl-2,2-dimethyl-oxazolidin-3-yl)-2-(biphenyl-4-yl-1H-pyrrol-3-yl)-ethanone, 2-acetoxy-2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester was hydrogenolyzed to provide in 61% yield 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid ethyl ester as a white solid, mp 77-78° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][C:8]=1[F:41].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:42])=[O:4])=[C:8]([F:41])[CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 5 h
Yield: 76.8 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.3 mL) was added to a solution of [4′-(1-ethyl-1-{4-[2-(1-hydroxy-cyclohexyl)-ethyl]-3-methyl-phenyl}-propyl)-3-fluoro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 115-(1); 45.6 mg, 0.0837 mmol) in methanol (0.8 mL), and the mixture was stirred for five hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (3% methanol/dichloromethane) to give the title compound (34.1 mg, 76%).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][N:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][N:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: CN1CCCC[C@H]1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 171 mg, 4.27 mmol) in DMF (4.00 mL) was added Intermediate A (175 mg, 1.07 mmol) and the reaction stirred for 20 min. Intermediate 62b (250 mg, 1.07 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for one hour. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC, using 2-10% [2M NH3 in MeOH] in DCM, to give the title compound (287 mg, 71%). LCMS (Method 1): Rt 1.64, m/z 378.2 [MH+].
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([C:25]1[N:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43](=[O:46])(=[O:45])[NH2:44])=[CH:33][CH:32]=2)[C:28]2[CH:47]=[C:48]([C:52]3[N:56]([CH3:57])[C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[N:53]=3)[CH:49]=[C:50]([CH3:51])[C:27]=2[N:26]=1)[CH2:23][CH3:24].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:22]([C:25]1[N:29]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[S:43]([NH:44][C:1](=[O:9])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)(=[O:45])=[O:46])=[CH:35][CH:36]=2)[C:28]2[CH:47]=[C:48]([C:52]3[N:56]([CH3:57])[C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[N:53]=3)[CH:49]=[C:50]([CH3:51])[C:27]=2[N:26]=1)[CH2:23][CH3:24]
Reactant: O=C(O)c1ccccc1
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 55 °C

Procedure:
145 mg of benzoic acid and 192 mg of carbonyldiimidazole are stirred in 1 ml of tetrahydrofuran for 2 hours at 50° C. To this is added a solution of 163 mg of 4'-[(2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-sulphamoyl-biphenyl, 0.133 ml of 1,8-diazabicyclo-[5.4.0]undec-7-ene and 1 ml of tetrahydrofuran and the mixture is maintained at 55° C. for 2.5 hours. Then 50 ml of ethyl acetate and 20 ml of 5% citric acid are added. The organic phase is dried with sodium sulphate and evaporated down. The residue obtained is chromatographed over silica gel with dichloromethane/ethanol (95:5).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC=CC=1>O.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.CCO>[CH3:17][C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=2)=[CH:27][CH:26]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: CCOC(=O)COCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)COCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 120 °C

Procedure:
Ethyl 2-(4-bromobenzyloxy)acetate (304 mg, 1.113 mmol), (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid hydrochloride (300 mg, 1.113 mmol), tetrakis(triphenylphosphine)palladium(0) (64.3 mg, 0.056 mmol) and 2M Na2CO3 (aq.) (1113 μL, 2.226 mmol) were added to a vial with benzene (2 mL) and EtOH (0.6 mL). The reaction was heated under microwave irradiation at 100° C. for an hour and 120° C. for 0.5 h. The reaction was diluted with H2O (1 mL) and extracted with EtOAc (3×2 mL). The combined organics were filtered through a plug of MgSO4. The solvent was evaporated and the residue was purified by column chromatography and prep LCMS to give the title compound. LCMS m/z=382.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.26 (m, 3H), 1.39 (d, J=6.4 Hz, 3H), 1.54-1.70 (m, 1H), 1.85-2.12 (m, 2H), 2.15-2.29 (m, 1H), 2.96-3.14 (m, 2H), 3.14-3.28 (m, 2H), 3.40-3.49 (m, 1H), 3.54 (d, J=20.3 Hz, 1H), 3.59-3.70 (m, 1H), 4.09-4.21 (m, 4H), 4.59 (s, 2H), 7.36-7.49 (m, 4H), 7.66 (d, J=7.71 Hz, 4H), 9.51-10.13 (m, 1H).