Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.II.[F:13]F.C(=O)(O)[O-].[Na+]>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:13][C:2]1[CH:3]=[N:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: c1ccc2nccnc2c1
Reactant: FF
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Product: Fc1cnc2ccccc2n1

Procedure:
A solution containing quinoxaline (15.6 g), 120 mmol) and iodine (30.5 g, 120 mmol) in CF2ClCFCl2 (150 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (165 mmol) as a 10% mixture in nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 40 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (300 ml), neutralised with sodium bicarbonate and continuously extracted with dichloromethane for 24 hours. The organic extracts were dried and evaporated to an oil (13.6 g). GC/MS analysis showed a 49% conversion of quinoxaline. The oil was purified by column chromatography on silica gel using dichloromethane as eluant to give pure 2-fluoroquinoxaline as a pale yellow oil (5.30 g, 62% based on 49% conversion); RF 0.53; δH (200 MHz; CDCl3 ; Me4Si) 7.7 ppm (2H, m), 7.9 (1H, m), 8.1 (1H, m), 8.67 (1H, d, JH,F 7.9, H-3); δF (250 MHZ; CDCl3 ; Me4Si) -75.1 ppm (s); δC (50.3 MHz, CDC13, Me4Si) 128.4 ppm (d, 4JC,F 1.6, C-8), 129.4 (s, C-7), 129.45 (s, C-6), 131.6 (s, C-5), 136.5 (d, 2JC,F 42.6, C-3), 139.72 (d, 3JC,F 10.9, C-8a), 141.52 (d 4JC,F 1.8, C-4a), 156.74 (d, 1JC-F 256.0, C-2); m/z (E1+) 148 (M+, 100), 129 (20), 121 (12), 103 (17), 76 (24), 50 (17); and 2,3-difluoroquinoxaline (0.27 g, 3%) as a pale yellow solid; RF 0.75; δH (400 MHz, CDCl3, Me4Si) 7.79 ppm (2H, m, Ar-H), 7.99 (2H, m, Ar-H); δC (50 MHz, CDCl3, Me4Si) 127.8 (s, C-8), 130.4 (s, C-7), 130.4 (s, C-7), 138.4 (d d, 3JC-F 5.4, C-4a), 146.1 (d d, 1JC-F 261.3,2JC-F 39.5, C-2); δF (235 MHz, CDCl3, CFCl3) -82.8 ppm (s); m/z (E1+) 166 (M+, 100%), 139 (11).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][CH2:21][O:22][CH3:23])([C:17](O)=[O:18])[CH2:13][CH2:12]1)(=[O:10])=[O:9].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([NH2:59])=[CH:55][CH:54]=1)[CH3:49].CN1CCOCC1>C1COCC1>[CH2:48]([O:50][C:51](=[O:60])[CH2:52][C:53]1[CH:54]=[CH:55][C:56]([NH:59][C:17]([C:14]2([CH2:20][CH2:21][O:22][CH3:23])[CH2:13][CH2:12][N:11]([S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:9])=[O:10])[CH2:16][CH2:15]2)=[O:18])=[CH:57][CH:58]=1)[CH3:49]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: COCCC1(C(=O)O)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCOC(=O)Cc1ccc(NC(=O)C2(CCOC)CCN(S(=O)(=O)c3ccccc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.6 %

Procedure:
1-(2-Chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid (2.82 g) were dissolved in THF (30 ml) under an argon atmosphere at RT and then sequentially treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (3.26 g), (4-amino-phenyl)-acetic acid ethyl ester (1.536 g) and N-methyl morpholine (1.04 ml). The reaction mixture was stirred 12 h at RT, and 1 h at reflux to complete the reaction. The mixture was partitioned between AcOEt and 1N HCl/water, the layers were separated; the organic layer was dried over sodium sulphate and then removed in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2/AcOEt, 19/1 to 9/1) to give the desired (4-{[1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carbonyl]-amino}-phenyl)-acetic acid ethyl ester (2.47 g) which was directly used in the next step.
Reaction SMILES: [C:1]([C:3]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)([CH2:10][CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH2:4][C:5](OCC)=[O:6])#[N:2].CCO.C([O-])(O)=O.[Na+]>O>[Cl:26][C:21]1[CH:20]=[C:19]([C:3]2([CH2:10][CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:1][NH:2][C:5](=[O:6])[CH2:4]2)[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: CCOC(=O)CC(C#N)(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CC(CCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Yield: 83.8 %

Procedure:
A solution of 8 g of the compound obtained in step B in 100 ml of 100° EtOH, 5 ml of water and 0.6 g of NaHCO3 is hydrogenated at atmospheric pressure and at RT. The catalyst is filtered off and the filtrate is evaporated under vacuum. The residue is extracted with DCM, the extract is washed with water and dried over MgSO4 and the solvent is evaporated off under vacuum to give 6 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][C:17]=1[C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1-chloro-3-methoxybenzene(823.7 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide the crude product. Purification by silica gel chromatography provided (2-chloro-4-methoxyphenyl)(4-chlorophenyl)methanone(1.1 g, 4.1 mmol). (2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanone was dissolved in AcOH (60 mL) and 49% HBr (60 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. This was dissolved in MeOH (30 mL) and THF (6 mL) and cooled to 0° C. Into the reaction mixture NaBH4 (235.5 mg, 6.2 mmol) was added. After 30 minutes the reaction was quenched with aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo. Without purification this was subjected to alkylation with 1,8-dibromoocatane (3.3 g, 12.3 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (45 mL). After 12h the reaction mixture was diluted with water (150 mL) and water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (746 mg, 10.5 mmol) and NaHCO3 (11.0 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.5 g, 3.3 mmol); 1H-NMR (300 MHz, CDCl3); 7.29-7.17 ppm (m, 5H), 6.84 (d, J=10.1 Hz, 1H), 6.74 (s, 1H), 5.98-5.80 (m, 2H), 5.31-5.15 (m, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.20-3.08 (m, 2H), 2.58-2.40 (m, 2H), 2.35 (s, 3H), 1.77-1.45 (m, 4H), 1.32-1.15 (m, 8H); 13C—NMR (75 MHz, CDCl3) 156.3 ppm, 138.3, 134.2, 131.8, 130.0, 129.6, 129.3, 116.2, 74.5, 68.8, 60.4, 43.8, 57.0, 29.6, 29.3, 28.1, 27.3, 25.9; ESI-MS calcd for C25H34Cl2NO2 [M+H]+: 450.2. found 450.2.
Reaction SMILES: [CH2:1]([S:13](Cl)(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[Cl:17][C:18]1[C:35]([Cl:36])=[CH:34][C:21]2[NH:22][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH2:31])[CH:30]=3)=[N:24][C:20]=2[CH:19]=1.O.Cl>N1C=CC=CC=1>[Cl:36][C:35]1[C:18]([Cl:17])=[CH:19][C:20]2[NH:24][C:23]([C:25]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([NH:31][S:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH:30]=3)=[N:22][C:21]=2[CH:34]=1
Reactant: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1N
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)ccc1OC
Temperature: 80 °C
Yield: 4 %

Procedure:
1-Dodecanesulfonyl chloride (0.38 g, 1.4 mmol) was added to a stirred suspension of 5-(5,6-dichloro-1H-benzoimidazol-2-yl)-2-methoxy-phenylamine from Step B (0.6 g, 1.4 mmol) in pyridine (6 mL) under an inert atmosphere, warmed briefly to 80° C. then stirred at room temperature. After approximately 20 hours the mixture was poured into water (60 mL), stirred, and acidified with aqueous HCl. After several hours the mixture was extracted with dichloromethane (60 mL, 30 mL) and the combined extracts were washed with water then 0.5 M sodium bicarbonate solution. A little saturated brine was added to assist with stratification. The organic phase was washed with saturated brine, dried over MgSO4, and stripped of solvent to leave the crude product as a crystalline residue. Recrystallization from acetonitrile followed by chromatography on silicagel in CHCl3/EtOAc (9:1) afforded the product (0.03 g), mp 203-204° C.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 43.6 %

Procedure:
101 mg of (13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoic acid was stirred under argon at room temperature for 25 hours with 2 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then concentrated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus producing 31 mg of the desired carboxylic acid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:19])[C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>Cl>[CH3:2][N:3]([CH3:19])[C:4]1([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2cccs2)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(c2cccs2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dimethyl-(8-thiophen-2-yl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (8.68 g) was dissolved in 7.5M hydrochloric acid (29 ml), stirred for 48 hours at room temperature and then extracted with diethyl ether (2×50 ml). The aqueous phase was rendered alkaline with 5M sodium hydroxide solution, while cooling with ice, extracted with dichloromethane (3×50 ml), dried and concentrated. 4-Dimethylamino-4-thiophen-2-yl-cyclohexanone was obtained as a yellow solid (5.66 g; m.p. 108-110° C.).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:23](=[O:25])[CH3:24])=[N:20][C:21]=1[Cl:22]>CN(C=O)C>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[C:21]([Cl:22])=[N:20][C:19]([C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(=O)c1ccc(CBr)c(Cl)n1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(CNCCC(=O)OC(C)(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-amino-propionic acid tert-butyl ester hydrochloride (1.5 eq) in DMF is added NaH (3.5 eq). The resulting mixture is stirred at room temperature for 15 minutes and a solution of 1-(5-bromomethyl-6-chloro-pyridin-2-yl)-ethanone (1 eq) in DMF is then added. After stirring for 3 hours, it is partitioned with 20% EtOAc/hexane and H2O. The organic layer is washed with brine and dried. After concentration, 3-[(6-acetyl-2-chloro-pyridin-3-ylmethyl)-amino]-propionic acid tert-butyl ester is isolated by flash column chromatography. MS: (ES+): 313.1 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[CH:3]1.[Cl-].[CH:8](=[N+:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[N:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: Cn1cccc1
Reactant: C(c1ccccc1)=[N+]1CCCC1
Agent: [Cl-]
Product: Cn1cccc1C(c1ccccc1)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-pyrrole and 1-benzylidene-pyrrolidinium chloride.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[CH3:55][C:56]1[C:60]([S:61](Cl)(=[O:63])=[O:62])=[C:59]([CH3:65])[O:58][N:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([S:61]([C:60]2[C:56]([CH3:55])=[N:57][O:58][C:59]=2[CH3:65])(=[O:63])=[O:62])[CH2:49][CH2:48]1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1S(=O)(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 17 %

Procedure:
The desired compound was prepared according to the procedure of Example A42 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 3,5-dimethylisoxazole-4-sulfonyl chloride as starting materials in 17% yield. LCMS for C29H32ClN8O4S (M+H)+: m/z=623.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[C:7](C(OCC)=O)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:19].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:18])=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[I:19]
Reactant: CCOC(=O)c1c(O)c2cc(I)c(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: C1COCCO1
Product: O=c1cc(O)c2cc(I)c(Cl)cc2[nH]1
Temperature: 80 °C
Reaction time: 72 h
Yield: 42.9 %

Procedure:
To a suspension of ethyl 7-chloro-4-hydroxy-6-iodo-2-oxo-1,2-dihydro-3-quinolinecarboxylate (Intermediate 100) (2 g, 5.08 mmol) in 1,4-dioxane (10 mL) was added concentrated hydrochloric acid (3 mL, 36.5 mmol) and the reaction mixture was stirred 72 h at 80° C. After cooling, the reaction mixture was evaporated and the resulting solid was filtered, washed with water and dried to give the title compound 7-chloro-4-hydroxy-6-iodo-2(1H)-quinolinone (700 mg, 2.177 mmol, 42.8% yield) as cream solid. LCMS: (M+H)+=322; Rt=2.26 min.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:19][CH:18]=2)[C@@H:13]1[C:31]1[CH:42]=[CH:41][C:34]([O:35][CH2:36][C:37]([O:39]C)=[O:38])=[CH:33][CH:32]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.CCN(CC)CC.[Li+].[Cl-]>CC#N>[Si:1]([O:8][C@H:9]([C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=1)[CH2:10][S:11][C@H:12]1[C:15](=[O:16])[N:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]#[C:24][CH2:25][NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:21][CH:22]=2)[C@@H:13]1[C:31]1[CH:32]=[CH:33][C:34]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:41][CH:42]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc([C@@H]2[C@@H](SC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(C#CCNS(C)(=O)=O)cc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H](CS[C@H]1C(=O)N(c2ccc(C#CCNS(C)(=O)=O)cc2)[C@@H]1c1ccc(OCC(=O)O)cc1)c1ccc(F)cc1
Temperature: 35 °C

Procedure:
Methyl {4-[(2R,3R)-3-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)ethyl]thio}-1-(4-{3-[(methylsulfonyl)amino]prop-1-yn-1-yl}phenyl)-4-oxoazetidin-2-yl]phenoxy}acetate (530 mg, 0.73 mmol) was dissolved in 15 ml MeCN. Water (0.2 ml), Et3N (1.0 ml, 7.2 mmol) and LiCl (630 mg, 14.9 mmol) were added and the mixture was stirred at 35° C. over night. The mixture was filtered and concentrated. The residue was extracted between EtOAc and 0.3 M KHSO4. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine (2×) and concentrated. The brown residue was purified by preparative HPLC on a C8 column (150×30 mm) using a gradient from 20-60% MeCN in 0.1 M ammonium acetate as eluent. The title compound was obtained in 170 mg (33%) as a slightly brownish solid. M/z: 711.2 (M−1). 1H-NMR (400 MHz, DMSO-d6) δ: −0.18 (s, 3H), −0.04 (s, 3H), 0.78 (s, 9H), 2.93 (ddd, 2H), 2.98 (s, 3H), 4.01 (d, 2H), 4.29 (d, 1H), 4.67 (s, 2H), 4.88-4.94 (m, 1H), 5.11 (d, 1H), 6.93 (d, 2H), 7.09-7.18 (m, 2H), 7.21 (d, 2H), 7.32-7.42 (m, 6H), 7.58 (t, 1H), 12.97 (brs, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[CH:8]3[CH2:14][CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[C:21]([CH:12]2[N:9]3[C:10]4[C:5]([NH:6][C:7](=[O:15])[CH:8]3[CH2:14][CH2:13]2)=[CH:4][CH:3]=[CH:2][CH:11]=4)[CH:20]=[CH:19][CH:18]=1
Reactant: O=C1Nc2ccc(Br)cc2N2CCCC12
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccccc2N2C1CCC2c1cccc(Cl)c1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
A solution of 8-bromo-1,2,3,3a-tetrahydro-5H-pyrrolo(1,2-a)quinoxalin-4-one (2.7 g, 10 mmol), 3-chlorophenyl boronic acid (1.6 g, 10 mmol), potassium carbonate (4 g, 30 mmol), and tetrakis(triphenylphosphine) palladium(0) (0.5 g, 0.43 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×60 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The crude product (1.5 g) was recrystallized from EtOAc/hexane to afford the title compound (0.2 g, 7%): mp 210° C.; MS (+APCI) m/z 299 ((M+H)+).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1CCCc2cc(-c3ccc(F)c(Cl)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chloro-4-fluorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ESI) m/z 275.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[C:35]=2[Cl:44])[CH2:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=1)(C)(C)C.Cl>O1CCOCC1>[Cl:44][C:35]1[C:36]([C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:18]([CH2:19][CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:17][CH2:16][CH2:15][O:14][C:10]1[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Yield: 96.1 %

Procedure:
To N-(3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-2,2-diphenylethyl-amino]-propoxy}-phenyl)-carbamic acid tert-butyl ester (492 mg, 0.77 mmol) dissolved in dioxane (5 mL) was added a 4.0 M solution of HCl in dioxane (5 mL). The solution was maintained for 20 hours after which the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed twice with saturated NaHCO3, dried over Na2SO4, and concentrated to give 0.4 g (0.74 mmol, 96%) of the title compound as a yellow oil. MS (ESI) 539.2
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1OCC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[CH3:39][O:40][C:41]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH2:53][CH2:54][OH:55])=[CH:45][CH:44]=1)=[O:42]>>[CH3:39][O:40][C:41]([C:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:46]([CH2:53][CH2:54][O:55][C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[S:17](=[O:19])(=[O:18])[NH:16][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:45][CH:44]=1)=[O:42]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCc1ccccc1
Reactant: COC(=O)c1ccc(CCO)c2ccccc12
Product: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1ccc(C(=O)OC)c2ccccc12

Procedure:
Synthesized by the Mitsunobu reaction between (S)-3-(4-Acetylamino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester from step 8 of Route J and 4-(2-hydroxyethyl)-naphthlene-1-carboxylic acid methyl ester from above. 1H NMR (400 MHz, CD3OD) 8.96(d, 1H), 8.16(dd, 2H), 7.71(d, 2H), 7.61(m, 2H), 7.55(d, 1H), 6.69(d, 1H), 5.57(d, 1H), 4.42(t, 2H), 4.21(d, 1H), 3.98(s, 3H), 3.72(t, 2H) 3.62(m, 1H), 3.42(m, 2H), 3.40(m, 1H), 3.14(m, 1H), 2.37(d, 2H), 2.16(s, 3H), 1.37(s, 9H), 1.00(t, 3H), 0.90(t, 3H).