Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[C:10]([C:13]1[CH:14]=[N:15][CH:16]=[C:17](Br)[CH:18]=1)([CH3:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:35][N:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([C:17]3[CH:16]=[N:15][CH:14]=[C:13]([C:10]([C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:20])([CH3:12])[CH3:11])[CH:18]=3)=[CH:35][N:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)OCc4ccccc4)c3)cnc21

Procedure:
6-[5-(1-Benzyloxycarbonyl-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is synthesized according to the procedure of Suzuki Coupling Method VI using 2-(5-bromo-pyridin-3-yl)-2-methyl-propionic acid benzyl ester and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (Intermediate G).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](O)=O)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C:17]([CH3:19])([CH3:18])[OH:20])[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCC(=O)O
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cc(Cl)ccc12
Product: CCOCc1nc2cnc3cc(Cl)ccc3c2n1CC(C)(C)O

Procedure:
Using the general method of Example 42, 7-chloro-4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline (18.5 g, 63 mmol, Example 82) was reduced and the resulting diamine reacted with ethoxyacetic acid to provide the desired product as a thick, green oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.Cl.[OH:21][C:22]1[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]2[C:23]=1[CH2:24][CH2:25][NH:26][CH2:27]2>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:15]([C:17]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:22]=4[OH:21])[CH2:27]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: O=C(O)c1nc(-c2cccnc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cccnc3)nc3ccccc13)C2
Yield: 16 %

Procedure:
Reaction of 2-(3-pyridinyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 84 (16% yield) as a light yellow solid. 1H NMR (300 MHz, CD3OD) δ 2.82 and 3.08 (2t, 2H), 3.58 and 4.17 (2t, 2H), 3.83 and 3.89 (2s, 3H), 4.45 and 5.03 (2s, 2H), 6.29 and 6.79 (2d, 1H), 6.71 and 6.92 (2d, 1H), 7.60-8.25 (m, 5H), 8.71-8.72 (m, 1H), 8.92-9.05 (m, 1H), 9.68 and 9.73 (2s, 1H); MS (ESI) m/z 413 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: COc1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Br)c(CBr)c1
Temperature: -10 °C
Yield: 70.4 %

Procedure:
A mixture of 2-bromo-5-methoxytoluene (20 g, 0.10 mol), N-bromosuccinimide (19.6 g, 0.11 mol), benzoyl peroxide (1 g, 4 mmol), and methylene chloride (200 mL) was irradiated for 18 hr with a flood lamp to effect gentle reflux. The mixture was then cooled to −10° C. for several hours and the solution was decanted away from the precipitated succinimide. The solution was concentrated and the residue was crystallized from chloroform/hexane to give the title compound (19.7 g, 70%) as pale yellow prisms: 1H NMR (CDCl3) δ 7.45 (d, J=8.9 Hz, 1 H, 6.99 (d, J=3 Hz, 1 H, 6.74 (dd, J=8.9, 3 Hz, 1 H), 4.55 (s, 2 H) 3.80 (s, 3 H).
Reaction SMILES: [CH:1]1([NH:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1)([O-:13])=[O:12]>>[CH:1]1([N:9]([OH:10])[C:21]([NH:20][C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: ONC1CCCCCCC1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)N(O)C1CCCCCCC1

Procedure:
Using the general method of Compound 36 Part C, cyclooctyl hydroxylamine (Compound 36 Part B, 1.0 g, 7.0 mmol) was reacted with 4-nitrophenyl isocyanate (1.2 g, 7.3 mmol) to provide 1.1 g of the desired product as a pale yellow solid, m.p. 143°-144° C. Analysis: Calculated for C15H21N3O4 : %C, 58.62; %H, 6.89: %N, 13.67; Found: %C, 58.5; %H, 7.56; %N, 13.32.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[OH:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:5]([O:19][CH2:20][CH:21]1[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reaction time: 8 h

Procedure:
A solution of tert-butylchlorodiphenylsilane (5.56 mL, 21.36 mmol) in DCM (20 mL) was added dropwise to a stirred solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (CAS no. 142253-56-3) (4.0 g, 21 mmol) and anhydrous N-ethyl-N-isopropylpropan-2-amine (9.1 mL, 53 mmol) in DCM (45 mL) cooled to 10° C., over a period of 2 minutes under nitrogen. The resulting solution was stirred at ambient temperature for 3 hours 4-dimethylaminopyridine (100 mg) was added and the reaction was left overnight. The reaction mixture was concentrated and diluted with EtOAc (75 mL), and washed sequentially with saturated NaHCO3 (25 mL), water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford the crude product (9.87 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.CCN(CC)CC.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]#[N:7]
Reactant: NC(=O)c1c(F)ccc(Br)c1Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1c(F)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2-chloro-6-fluorobenzamide (3.56 mmol) in 50 mL DCM were added 1.5 mL Et3N followed by trifluoromethanesulfonic acid anhydride (7.11 mmol) at 0° C. The ice bath was removed and the reaction mixture was stirred at RT. After 30 min, water was added and the mixture was extracted with DCM (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo to obtain the desired compound as brown solid.
Reaction SMILES: O[CH2:2][C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)C[C@H](C)C1=CC(=O)CC2.C[O-].[C:26]1([Si:32]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:33][CH2:34][C@@:35]23[C@@H:52]4[C@H:43]([C@H:44]5[C@@:48]([CH2:50][CH2:51]4)([CH3:49])[C:47](=[O:53])[CH2:46][CH2:45]5)[CH2:42][CH2:41][C:40]2=[CH:39][C:38](=[O:54])[CH2:37][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:2][C@H:36]1[C@@:35]2([CH2:34][O:33][Si:32]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:40]([CH2:41][CH2:42][C@@H:43]3[C@@H:52]2[CH2:51][CH2:50][C@@:48]2([CH3:49])[C@H:44]3[CH2:45][CH2:46][C:47]2=[O:53])=[CH:39][C:38](=[O:54])[CH2:37]1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Agent: C[O-]
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Following essentially the same procedure but substituting 19-hydroxhy-1β-methyl-4-androstene-3,17-dione and 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 1β-methyl-19-triphenylsiloxy-4-androstene-3,17-dione and 6α-methyl-19-triphenylsilioxy-4-androstene-3,17-dione.
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:6]1([C@@H:2]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCCCCBr
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1)N1CCCC1

Procedure:
To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1,4-dibromobutane (1.57 g, 0.727 mmol) and sodium carbonate (2.103 g, 19.85 mmol) was added ethanol (40 mL) and the resultant mixture heated at 100° C. for 65 hours. After cooling, the resultant solid was removed by filtration and washed with ethanol. The filtrate was concentrated, and then dissolved in ethanol then a solution of 4N aqueous hydrochloric acid added until the pH of the solution was 3. The resultant solid was removed and discarded. The filtrate was concentrated and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound. MS (ESI) m/z 206 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][NH:16][CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>ClCCl>[NH2:2][C:3]1[C:8]2=[C:9]([C:19]3[CH:20]=[CH:21][C:22]4[C:26]([CH:27]=3)=[N:25][N:24]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:23]=4)[CH:10]=[C:11]([C:12]([CH:14]3[CH2:18][CH2:17][N:16]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:15]3)=[O:13])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ncnn2c(C(=O)C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(C(=O)c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Reaction time: 18 h
Yield: 24.5 %

Procedure:
[4-Amino-5-(2-benzyl-2H-indazol-6-yl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-pyrrolidin-3-yl-methanone hydrochloride salt (89 mg, 0.19 mmol) was dissolved in dichloromethane (1 mL) and triethylamine (0.079 mL, 0.56 mmol) was added, followed by methanesulfonyl chloride (0.022 mL, 0.28 mmol). The mixture was stirred at it for 18 h and then at 50° C. overnight. The mixture was concentrated, diluted with MeOH, filtered and the filtrate purified by HPLC eluting with 20-95% gradient acetonitrile/water to afford 24 mg (25%) of the title compound. 1H-NMR (CD2Cl2-d2) 8.13-8.06 (m, 2 H), 7.81 (dt, 1H), 7.77-7.76 (m, 1 H), 7.43 (s, 1H), 7.42-7.33, (m, 5 H), 7.19 (dd, 1 H), 5.64 (s, 1 H), 4.61-4.53 (m, 1 H), 3.74-3.65 (m, 2 H), 3.54-3.44 (m, 1 H), 3.39-3.31 (m, 1 H), 2.89 (s, 1 H), 2.46-2.28 (m, 2 H); LC-MS [M+H]+=516.2, RT=2.88 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:17][CH2:18][CH3:19])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CCCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 99.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and propylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (0.37 g, 91%) was provided after purification. MS (ESI) m/z 362. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:45]2[N:46]=[C:47]([NH:50]C=O)[S:48][CH:49]=2)[C:7]([NH:9][C@@H:10]2[C:43](=[O:44])[N:12]3[C:13]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[C:14]([CH2:17][S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[NH2:50][C:47]1[S:48][CH:49]=[C:45]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:43](=[O:44])[N:12]3[C:13]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[C:14]([CH2:17][S:18]/[CH:19]=[CH:20]\[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:46]=1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CS/C=C\c4cccnc4)CS[C@H]23)cs1
Temperature: 35 °C
Yield: 63.4 %

Procedure:
To a suspension of benzhydryl 7β-[2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (1.32 g) in methanol (30 ml) was added concentrated hydrochloric acid (0.44 ml) and the mixture was stirred at 35° C. for an hour. The mixture was poured into a mixture of ethyl acetate and ice-water and adjusted to pH 7 with saturated aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride and water successively and concentrated in vacuo to give benzhydryl 7β-[2-(2-aminothiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-[(Z)-2-(3-pyridyl)vinylthiomethyl]-3-cephem-4-carboxylate (syn isomer) (806 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([NH2:12])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.C([O:25][C:26](=O)/[CH:27]=[C:28](/[O:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[Cl:39])\[CH2:29]Br)C>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([N:12]1[CH2:29][C:28]([O:31][C:32]2[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=2[Cl:39])=[CH:27][C:26]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)/C=C(\CBr)Oc1cc(Cl)ccc1Cl
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 15.2 %

Procedure:
To a stirred solution of (S)-2-amino-3-cyclohexyl-propionic acid methyl ester (750 mg, 0.004 mol) in N,N-dimethylformamide (10 mL) was added N,N-diisopropylethylamine (2.6 g, 0.02 mol) slowly at room temperature, under nitrogen. The resulting mixture was stirred for 5 min and then treated with (E)-4-bromo-3-(2,5-dichloro-phenoxy)-but-2-enoic acid ethyl ester (1.5 g, 0.004 mol) and the reaction mixture was heated at 110° C.-120° C. for 16 h. After this time, ice water was added and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (silica gel (100-200 mesh)) afforded (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (250 mg, 15%) as yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([O:27]C)=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:24])[CH3:23])[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:25]([OH:27])=[O:26])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N(C1CCC(C)(C)CC1)[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
Methyl (2S,4S)-1-BOC-4-[acetyl(4,4-dimethylcyclohexyl)amino]pyrrolidine-2-carboxylate (0.98 g, 2.47 mmol) obtained in Step B, was dissolved in MeOH (8 mL) and water (1.6 mL). LiOH (0.18 g, 7.52 mmol) was added thereto at 0˜5° C. After the reaction mixture was stirred at room temperature for 3 hours and concentrated in vacuo, the obtained residue was diluted with water and the solution was extracted with EtOAc. The extracted organic solution was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (0.92 g, 97%).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17])=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH2:19][CH3:20])[C:16]([Cl:4])=[O:17])=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C(=O)O)c1ccc(OC)cc1
Solvent: ClCCl
Product: CCC(C(=O)Cl)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Oxalyl chloride (12 mL of a 2.0M solution in CH2Cl2) was added under nitrogen to a solution of 2-(4'-methoxyphenyl)butyric acid (4.66 g, 24 mmol) in 25 mL of CH2Cl2 and stirred at room temperature overnight. The volatiles were removed under vacuum and the residue was distilled to afford 4.46 g (87%) of pure 2-(4'-methoxyphenyl)butyryl chloride. 1H NMR (CDCl3) δ0.919 (t, 3H, J=7.4 Hz), 1.78-1.92 (m, 1H), 2.13-2.27 (m, 1H), 3.81 (s, 3H), 3.83 (t, 1H, J=7.6 Hz), 6.91 (d, 2H, J=8.8 Hz), 7.21 (d, 2H, J=8.7 Hz); 13C NMR (CDCl3) δ11.43, 26.26, 55.14, 64.21, 114.50, 127.86, 129.65, 159.75, 175.48.
Reaction SMILES: [Li][C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2S(=O)(=O)C3C(=CC=CC=3)[O:23][C:22]=2[CH:21]=CC=1.C(=O)C>>[OH:23][CH:22]([C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: [Li]c1cccc2c1S(=O)(=O)c1ccccc1O2
Reactant: O=S1(=O)c2ccccc2Oc2ccccc21
Agent: CC=O
Product: CC(O)c1cccc2c1S(=O)(=O)c1ccccc1O2
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
To a batch of 1-lithiophenoxathiin 10,10-dioxide, prepared according to the procedure of Example 1B from 44 g of phenoxathiin 10,10-dioxide chilled to ≤-50° C. in a dry ice/acetone bath, was slowly added chilled acetaldehyde (20.37 g). The reaction mixture was maintained at -50° C. during the addition which took 45 min. It was then allowed to warm to room temperature, and the solvent was removed under reduced pressure. The yellow-orange residue was stirred overnight with 0.5 N hydrochloric acid (259 mL), filtered and washed with water (500 mL). It was then washed throughly with ethanol (1.5 L), filtered and dried to give 1-(1-hydroxyethyl) phenoxathiin 10,10-dioxide (41 g) which was sufficiently pure for the next step (conversion to 1-ethylphenoxathiin 10,10-dioxide).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:9])[O:4][N:3]=1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(OCC)(=O)C>[C:31]1([S:37]([O:1][C:2]2[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=2)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Cc1cc(O)no1)OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1cc(OS(=O)(=O)c2ccccc2)no1
Reaction time: 1 h

Procedure:
To a solution of 1.55 g (5 mmoles) of benzhydryl 3-hydroxyisoxazol-5-ylacetate in 20 ml of ethyl acetate were added 0.71 ml (5.1 mmoles) of triethylamine and 0.65 ml (5.05 mmoles) of benzenesulphonyl chloride. After stirring the mixture for 1 hour, it was washed with water and then dried. The solvent was distilled off to give the benzhydryl ester of the title compound quantitatively. The ester was then treated in the same manner as described in Preparation 5, affording 1.30 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:15])=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:16](OC)(OC)(OC)[CH3:17]>C(O)(C(F)(F)F)=O>[CH:9]1([N:8]2[C:7]3=[N:6][C:5]([OH:15])=[CH:4][CH:3]=[C:2]3[N:1]=[C:16]2[CH3:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(O)nc1NC1CCCCC1
Reactant: COC(C)(OC)OC
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(O)nc2n1C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
5-Amino-6-(cyclohexylamino) pyridin-2-ol (0.1 g, 0.482 mmol) was dissolved in trimethyl orthoacetate (3.0 mL, 27.4 mmol). Several drops of TFA were added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residues were diluted with water/acetonitrile (1:1). The mixture was purified via HPLC to give the title compound (0.006 g). LCMS m/z=232.30 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 1.43-1.5 (m, 1H), 1.53-1.63 (m, 2H), 1.83 (d, J=11.87 Hz, 1H), 2.01 (d, J=10.99 Hz, 4H), 2.64-2.74 (m, 2H), 2.89 (s, 3H), 4.51-4.57 (m, 1H), 6.90 (d, J=8.8 Hz, 1H), 8.0 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[S:9][C:10]([F:13])([F:11])[F:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(Br)cc1SC(F)(F)F
Reactant: BrCc1ccccc1
Product: FC(F)(F)Sc1cc(Br)ccc1OCc1ccccc1
Reaction time: 1 h

Procedure:
1-Benzyloxy-4-bromo-2-trifluoromethylthiobenzene was prepared from 4-bromo-1-hydroxy-2-trifluoromethylthiobenzene following Method C. The reaction was conducted at 50° C. for 1 h using benzyl bromide as an alkylating agent and the resulting product was purified by column chromatography using hexanes as an eluent to afford 1-benzyloxy-4-bromo-2-trifluoromethylthiobenzene in 63% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:34](=[O:35])[CH2:33][O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)CCCCCOc1ccc(N)cc1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(=O)CCCCCOc1ccc(NC(=O)COCc2ccccc2)cc1
Reaction time: 12 h
Yield: 22.2 %

Procedure:
To a mixture of 6-(4-aminophenoxy)-hexanoic acid methyl ester 17 (25 g, 105 mmol) and triethylamine (21.4 g, 211.6 mmol) in acetone (200 ml) at 0° C. was added dropwise benzyloxy acetyl chloride (25 g, 135.5 mmol) followed by stirring at room temp. for 12 hrs. The solids were filtered off, acetone distilled off and water (100 ml) added. Crude 53 was extracted into chloroform, washed with 5% sodium bicarbonate solution (2×100 ml), then water (100 ml), dried over sodium sulphate and distilled. Crude 53 was purified by column chromatography on silica gel using benzene as eluant to get pure 53 (9 g, 22.2%), an off-white powder with a m.p. between 46-49° C.