Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][C:4]([CH3:8])([CH3:5])[CH3:3])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1Br
Temperature: -30 °C
Reaction time: 144 h
Yield: 190 %

Procedure:
A mixture of 3-bromo-4-methylbenzoic acid (10.75 g, 50 mmol) in dry ether (50 mL) in a glass bomb was cooled to −30° C. and isobutylene gas was bubbled in to give a total reaction volume of approximately 150 mL. Trifluoromethanesulfonic acid (0.22 g, 2.5 mmol) was added dropwise to the stirred mixture, and the bomb was sealed. The reaction was allowed to warm to RT and was stirred for 6 d. The bomb was opened carefully, and 5% sodium bicarbonate (50 mL) was added slowly. The mixture was allowed to stir for 15 min and ether (250 mL) was added. The layers were separated and the organic layer was washed with 5% sodium bicarbonate (2×50 mL) and then with brine (50 mL). Drying (magnesium sulfate) and concentration gave the title compound (12.88 g, 95%) as a yellow oil. TLC Rf 0.68 (toluene); 1H NMR (250 MHz, CDCl3) δ8.13 (d, J=1.7 Hz, 1 H), 7.81 (dd, J=7.9, 1.7 Hz, 1 H), 7.27 (d, J=7.9 Hz, 1 H), 2.44 (s, 3H), 1.59 (s,9 H); IR (CCl4) 1715, 1368, 1297, 1255, 1170, 1123, 1115 cm−1; MS(ES) m/e 273.0 [M+H]+, 271.0 [M+H]+, 214.8 [M+H−C4H8]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][N:8]=1.[CH3:14][C:15]1([CH3:26])[CH2:20][C:19](=[O:21])[CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:19]2([OH:21])[CH2:18][CH2:17][CH:16]([C:22]([O:24][CH3:25])=[O:23])[C:15]([CH3:14])([CH3:26])[CH2:20]2)=[N:8][CH:9]=1
Reactant: COC(=O)C1CCC(=O)CC1(C)C
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CCC(O)(c2ccc(Br)cn2)CC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi was added dropwise to a solution of 2,5-dibromopyridine in toluene (30 mL) at −78° C. The reaction mixture was stirred for 1 hour at −78° C., then a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate in toluene (5 mL) was added. The reaction mixture was warm to room temperature, quenched with saturated aqueous ammonium chloride, extracted with CH2C12 (3×), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford methyl 4-(5-bromopyridin-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate as a colorless oil. MS ESI calc'd for C15H21BrNO3 [M+H]+ 342 and 344. found 342 and 344.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[CH2:17][C:16]1([CH3:50])[CH3:49])=O)(C)(C)C>C(Cl)Cl>[CH3:50][C:16]1([CH3:49])[NH:15][CH2:20][CH2:19][N:18]([CH2:21][C:22]2[N:23]([CH3:48])[C:24]3[C:29]([N:30]=2)=[C:28]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:27]=[C:26]([N:37]2[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=[C:38]2[CH2:46][CH3:47])[N:25]=3)[CH2:17]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)n(C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (530 mg, 1.35 mmol), 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.63 mmol) and molecular sieves (4 Å, powdered, 2.5 g) in DCE (30 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (427 mg, 2.02 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10) to give 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH before the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford 552 as a cream solid (144 mg, 22%). LCMS (Method I): RT=2.56 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29 (m, 2 H); 4.35 (m, 4 H); 3.92-3.83 (m, 7 H); 3.70 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.97 (m, 2 H); 2.47 (m, 2 H); 2.28 (s, 2 H); 1.49-1.42 (m, 3 H) and 1.19 (s, 6 H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24]O)=[O:15])=[CH:4][CH:3]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24][N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(C(=O)N2CC3CCCC3C2CN2C(=O)c3ccccc3C2=O)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (1 eq), phthalimide (2 eq) and triphenylphosphine (3 eq) in THF (56 mL) was cooled to 0° C. and added with DIAD (5 eq) dropwise. The resulting suspension was allowed to warm to rt gradually and stirred overnight, concentrated in vacuo to a brown oil. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was purified by chromatography on silica gel (EtOAc/hex) to give the title compound as a clear oil. MS (ESI) 490.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]>N1CCCCC1.[Cu]I.[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>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCC
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCC#Cc1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 87.2 %

Procedure:
A solution of 10.0 g (54.05 mmol) of 3-bromo-benzaldehyde in 150 ml of piperidine was treated at RT with 1.029 g (5.40 mmol) of copper(I)iodide and 6.246 g (5.40 mmol) of tetrakis-(triphenylphosphine)-palladium and the mixture was then warmed up to 60° C. After 10 min, a solution of 9.30 ml=6.66 g (81.07 mmol) of hex-1-yne in 150 ml of piperidine was added drop by drop during 1 hour. After 30 min, the oil bath temperature was steadily increased to 80° C. The reaction mixture was then stirred at 80° C. for 15 hours and subsequently cooled down to RT. The solvent was evaporated and the residue poured into crashed ice, acidified with HCl (37%) to pH 2-3 and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (n-heptane/EtOAc 1:0 to 97:3) to give 8.78 g (87%) of the title compound as yellow oil. MS: 186.2 (M+).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[Cl:19][CH:20](O)[CH3:21]>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:21][CH2:20][Cl:19])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Reactant: CC(O)Cl
Product: C=CCOC(=O)NC1CC(=O)OC1OCCCl
Yield: 34.9 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 g, 20 mmol) as described for 40 using chloroethanol (4.05 mL, 60 mmol) to afford 1.84 g (35% yield) of the title compound as a mixture of epimers. For the anti-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.42 (dd, J=18.1 Hz, 1H), 3.00 (dd, J=18.1, 7.8 Hz, 1H), 3.63 (m, 2H), 3.85 (m, 1H), 4.02 (m, 1H), 4.23 (m, 1H), 4.57 (br s, 2H), 5.17 (br s, 1H), 5.22 (d, H=11.5 Hz, 1H), 5.29 (d, J=16.8 Hz, 1H), 5.44 (s, 1H), 5.89 (m, 1H) ppm; LC-MS (ES+) m/e=264 (M+H). For the syn-diastereomer: 1H-NMR (500 MHz, CDCl3) δ 2.47 (dd, J=17.3, 10.7 Hz, 1H), 2.83 (dd, J=17.3, 8.4 Hz, 1H), 3.65 (m, 2H), 3.83 (m, 1H), 4.11 (m, 1H), 4.57 (m, 3H), 5.22 (d, H=10.4 Hz, 1H), 5.30 (d, J=17.2 Hz, 1H), 5.33, (m, 1H), 5.47 (d, J=5.2 Hz, 1H), 5.89 (ddt, J=17.1, 11.0, 5.4 Hz, 1H) ppm; LC-MS (ES+) m/e=264 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.Cl.Cl.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][C:25]4[CH:37]=[C:38]([O:42][CH3:43])[C:39]([O:40][CH3:41])=[C:23]([O:22][CH3:21])[CH:24]=4)[CH:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29]3)=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Reactant: COC(=O)C1CNCCN1Cc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)C2=Cc3cc(OC)c(OC)cc3CCC2)CCN1Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In dichloromethane (18 ml) is dissolved 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (1.44 g). The solution is added dropwise taking 5 minutes, while stirring at 0° C., to a mixture of methyl 1-(3,4,5-trimethoxybenzyl)piperazine-2carboxylate dihydrochloride (2.16 g), triethylamine (2.5 g) and dichloromethane (25 ml). The reaction mixture is stirred for one hour at room temperature, and then poured into ice-water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone =3:3:1) to afford methyl 4-(2 3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -1-(3,4,5-trimethoxybenzyl)piperazine -2- carboxylate, which is identical with the product obtained in Working Example 25, as a colorless oily product (2.2 g).
Reaction SMILES: [C:1]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13]OS(C3C=CC(C)=CC=3)(=O)=O)[N:11]=2)[CH:2]=1.C([O:34][C:35](=[O:53])[C:36]([CH3:52])([O:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)C>C(O)C>[C:1]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:9]([CH3:25])=[C:10]([CH2:12][CH2:13][O:44][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][C:36]([CH3:52])([O:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[C:35]([OH:34])=[O:53])=[CH:43][CH:42]=3)[N:11]=2)[CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Solvent: CCO
Product: Cc1oc(-c2cccc(-c3ccccc3)c2)nc1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)O)cc1
Temperature: 55 °C
Yield: 25 %

Procedure:
Toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (0.132 mmol) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (see Ex. 1, Part C) (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue redissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by massirected HPLC to produce the product as a white solid (25%). MS [EI+] 534 (M+H)+, 566 (M+Na)+, [EI−] 532 (M−H)+; HPLC: T=3.26 min, purity 97%.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([OH:19])=O)[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29](=[O:36])[NH:28][C:27]1=[O:37].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:23])[F:25])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:33]3[CH2:32][CH2:31][C:30]4([NH:26][C:27](=[O:37])[NH:28][C:29]4=[O:36])[CH2:35][CH2:34]3)=[O:19])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1NC(=O)C2(CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in DMF (2.0 mL) were added 1,3,8-triazaspiro[4.5]decane-2,4-dione (34 mg, 0.2 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 2 h, the solvent was removed under reduced pressure and the crude product was purified by PrepHPLC to give (S)-8-(2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione (32 mg) in 46% yield. MS (ESI) 527 (M+H); Rf=1.66.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[Cl:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Product: O=C(Nc1cc(C(F)(F)F)ccc1Cl)c1cc(Cl)ccc1O
Yield: 49.1 %

Procedure:
Using 5-chlorosalicylic acid and 2-chloro-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC(=O)OCC>[Br:5][C:3]1[N:11]=[C:10]([C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([Cl:6])[CH:8]=2)[O:1][N:2]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: ON=C(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nc(Br)no2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H)
Reaction SMILES: CC(C)([O-])C.[K+].Cl.[NH2:8][OH:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1>CO>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([C:15](=[N:8][OH:9])[NH2:16])=[CH:13][CH:12]=1
Reactant: NO
Reactant: N#Cc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: NC(=NO)c1ccc(Br)cc1
Yield: 109.4 %

Procedure:
To a stirred solution of ice cooled methanol (115 ml), under argon, was added potassium tert-butoxide (10.12 g. 0.09 mol), portionwise. After stirring for 5 minutes hydroxylamine hydrochloride (6.71 g, 0.097 mol) was added in one portion. After stirring for 1 hour at room temperature a slurry of 4-bromobenzonitrile, (10.88 g, 0.06 mol) in methanol (150 ml) was added. The mixture was then heated at reflux for 4 hours, cooled and filtered. The filtrate was evaporated in vacuo to give the title compound as a colourless solid (14.12 g, quant.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:29])[C:5]([F:28])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:9]3)[CH:7]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[PH4+].C(=O)(O)[O-].[Na+].[CH3:52][O:53][C:54]1[N:55]=[CH:56][C:57]([C:60](O)=[O:61])=[N:58][CH:59]=1>C(Cl)Cl>[F:28][C:5]1[C:4]([F:29])=[CH:3][C:2]([NH:1][C:60]([C:57]2[CH:56]=[N:55][C:54]([O:53][CH3:52])=[CH:59][N:58]=2)=[O:61])=[CH:7][C:6]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH:17]([F:19])[F:18])[C@H:13]1[CH2:12][S:11][C:10]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[N:9]2
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)F)[C@H]2CS1
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](C(F)F)[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
tert-butyl ((4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(difluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate, synthesized in preparation example 1-(13), (100 mg) was dissolved in DCM (2 mL) and 5-methoxypyrazine-2-carboxylic acid (50 mg), N,N-diisopropylethylamine (100 mg) and (1H-benzotriazol-1-yloxy)tripyrrolidin-1-yl)phosphonium hexafluorophosphate (175 mg) were added. The reaction mixture was stirred at RT for 3 days, and sodium bicarbonate (sat., aq., 25 mL) was added. The mixture was extracted with EtOAc (2×40 mL), the combined organic portions were dried over MgSO4, evaporated and purified by silica gel chromatography (EtOAc/hexanes gradient) to afford the title compound (108 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 9H), 2.82 (dd, J=13.5, 3.4 Hz, 1H), 3.08 (d, J=12.9 Hz, 1H), 3.33-3.45 (m, 1H), 3.84-3.93 (m, 1H), 4.10 (s, 3H), 4.46-4.65 (m, 2H), 5.97 (dt, J=3.8, 56.6 Hz, 1H), 7.08 (br. s., 1H), 7.27-7.36 (m, 1H), 8.14 (ddd, J=11.6, 7.0, 2.7 Hz, 1H), 8.20 (d, J=1.3 Hz, 1H), 9.04 (d, J=1.3 Hz, 1H), 9.55 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](Cl)=[O:34])[C:27]=2[N:26]=[CH:25]1.CCN(CC)CC.O>C(Cl)Cl>[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([N:13]3[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]4[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:8][C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:11][CH2:12]3)=[O:34])[C:27]=2[NH:26][CH:25]=1
Reactant: O=C(Cl)c1cccc2[nH]cnc12
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2cccc3nc[nH]c23)CC1
Yield: 54655828 %

Procedure:
To a solution of COMPOUND 249 (0.100 g, 0.322 nmol) in CH2Cl2 (5 mL) was added 1H-benzoimidazole-4-carbonyl chloride (0.118 g, 0.653 mmol) (White, A. W. et al. J. Med. Chem. 2000, 43, 4084-4097) and Et3N (0.37 g, 0.37 mmol). After the mixture was stirred overnight water (10 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over anhydrous Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on silica gel columns (column 1, 6:1 EtOAc/MeOH; column 2, 100:5:1 CH2Cl2/MeOH/NH4OH), affording a white solid (0.080 g, 56%). Conversion to the HBr salt using General Procedure D gave a white solid. 1H NMR (D2O) δ 1.55-1.84 (m, 2H), 1.95-1.99 (m, 1H), 2.18-2.22 (m, 1H), 2.45 (s, 6H), 2.88-3.20 (m, 3H), 3.72-3.77 (m, 1H), 4.32 (s, 4H), 4.63-4.70 (m, 1H), 7.61-7.67 (m, 2H), 7.74-7.80 (m, 2H), 7.89-7.93 (m, 1H), 8.28 (d, 2H, J=8.1 Hz), 8.50 (d, 2H, J=5.7 Hz), 9.20 (s, 1H); 13C NMR (D2O) δ 17.41, 27.50, 28.20, 42.48, 47.56, 51.01, 60.02, 117.02, 121.50, 125.51, 126.16, 127.09, 127.71, 131.38, 137.93, 138.77, 140.71, 148.67, 151.08, 167.43. ES-MS m/z 455 (M+Na). Anal. Calcd. for C27H30N6O.3.5HBr.0.25H2O.0.3C4H10O: C, 42.07; H, 5.20; N, 10.44; Br, 34.74. Found: C, 41.86; H, 5.18; N, 10.39; Br, 34.98.
Reaction SMILES: [S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[OH:6][C@H:7]1[O:14][C@@H:13]2[CH2:15][O:16][C@@H:10]([C@H:11]2[OH:12])[C@H:8]1O>>[S:1]([O:5][C@H:8]([C@H:10]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]1[OH:12])[CH:7]=[O:6])([OH:4])(=[O:3])=[O:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: O[C@@H]1[C@H]2OC[C@@H](O[C@@H]1O)[C@@H]2O
Product: O=C[C@H](OS(=O)(=O)O)[C@H]1OC[C@@H](O)[C@@H]1O

Procedure:
Carrageenans having a moleculr weight of from 100.000 to 800.000 Dalton are known; approximately 25% sulfate-content; various types: kappa-carrageenan: comprised of alternating 1,3 or 1,6, respectively, linked 3,6-anhydro-α-D-galactose and D-galactose-4-sulfate; gel-forming; only partially oxidizable lambda carrageenan: α-1,3-glycosidically linked D-galactose-2(4)-sulfate residues and 1,4-linked D-galactose-2,6-disulfate residues and 1,4-linked-D-galactose-2,6-disulfate residues; does not gel; and still partially oxidizable at C-6: i-carrageenan: from D-galactose-4-sulfate formed in 1,3-linkage and 3,6-anhydro-D-galactose-2-sulfate formed in 1,4-linkage; forms gel with Ca2+.