Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: 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.[CH2:34]([O:41][C:42](=[O:69])[NH:43][CH2:44][C:45](=[O:68])[NH:46][CH:47]([CH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[CH:54]=1)[CH:48]([OH:51])[CH2:49]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[O-][Mn](=O)(=O)=O.[K+]>C(Cl)(Cl)Cl>[CH2:34]([O:41][C:42](=[O:69])[NH:43][CH2:44][C:45](=[O:68])[NH:46][CH:47]([CH:48]1[CH2:49][O:51]1)[CH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[C:55]([O:60][CH2:61][C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH:54]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C(CNC(=O)OCc1ccccc1)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C(O)CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=C(CNC(=O)OCc1ccccc1)NC(Cc1cc(F)cc(OCc2ccccc2)c1)C1CO1
Reaction time: 8 h

Procedure:
In flame-dried glassware is prepared a solution of triphenylphosphine (0.291 g, 1.11 mmol, 1.10 eq.), diisopropylazodicarboxylate (0.22 mL, 1.11 mmol, 1.10 eq.) in anh. chloroform (2.5 mL). The product of Step 1 is added (0.500 g, 1.01 mmol, 1.00 eq.) with stirring under N2 overnight. The reaction is (complete as monitored by TLC; 35% EtOAc/Hexanes, KMnO4 stain) concentrated in vacuo to yield crude products as an amber oil. Calculate mass for C27H27FN2O5: 478.19. Mass found for C27H27FN2O5: (LCMS) ES+: 478.8 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].N[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O>>[C:14]([CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])[C:7]([OH:9])=[O:8])(=[O:16])[CH:13]=[CH:12][C:11]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCCCC(=O)O
Reactant: NCCCC(=O)O
Product: NCCCCC(C(=O)O)C(=O)C=Cc1ccccc1
Yield: 77 %

Procedure:
Using 6-aminocaproic acid in lieu of γ-aminobutyric acid, the title compound was synthesized following essentially the procedure described in Example 14. Yield 77%, m.p. 91.6-92.30C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=S.C([O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[CH:17]=1)C.CC(C)N=C=NC(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:15]([OH:24])=[O:14])=[CH:17][C:18]=2[N:23]=1
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 2 h

Procedure:
A mixture of 1,3-dichloro-2-isothiocyanato-benzene (5.66 g, 27.8 mmol) and 3,4-diamino-benzoic acid ethyl ester (5.00 g, 27.8 mmol) in 40 mL DMF was stirred for 2 h. DIC (4.40 mL, 28.2 mmol) was added and stirred overnight at ambient temperature. The mixture was stirred for 30 min at 80° C., diluted with water and concentrated i.vac. The residue was taken up in ethanol and 60 mL 1 M aq. NaOH was added and stirred overnight at reflux. Ethanol was evaporated and the aq. phase was filtered. The filtrate was acidified with formic acid, cooled, filtered and dried.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[NH:19][C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl[CH2:26][CH2:27][CH2:28][CH2:29][P:30]([O:35][CH2:36][CH3:37])(=[O:34])[O:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:7]([O:6][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH2:26][CH2:27][CH2:28][CH2:29][P:30](=[O:34])([O:35][CH2:36][CH3:37])[O:31][CH2:32][CH3:33])[C:18](=[O:23])[N:17]([CH3:24])[C:16]=2[N:15]=[CH:14]1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCOP(=O)(CCCCn1cnc2c1c(=O)[nH]c(=O)n2C)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2CCCCP(=O)(OCC)OCC)n(C)c1=O)OCC
Temperature: 70 °C

Procedure:
8 g (0.022 mol) of 7-(4-diethylphosphonobutyl)-3-methylxanthine (according to Example 24) were suspended in 100 ml of DMF, treated with 6.13 g (0.027 mol) of diethyl 4-chlorobutanephosphonate and 3.7 g (0.028 mol) of activated potassium carbonate and heated at 70° C. for 4 hours. The product was then filtered, the filtrate was concentrated under reduced pressure and the oily residue which remained was chromatographed on a silica gel column (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][CH:7]=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(CCCO)C1CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCC(=O)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
230 mg (1.79 mmol) of 1-cyclopropyl-4-hydroxy-1-butanone was dissolved in 7 ml of dichloromethane, and 580 mg (2.69 mmol) of pyridinium chlorochromate was added thereto, followed by stirring for 1 hour at room temperature. To the reaction solution was added diethyl ether, the mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; diethyl ether alone) to give 176 mg of the title compound as a pale yellow oil (yield: 78%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Cl[CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]>CN(C=O)C>[C:11]1(=[O:20])[N:10]([CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]12
Reactant: O=C1c2ccccc2C(=O)N1CCl
Reactant: Oc1ccncc1
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1COc1ccncc1
Temperature: 25 °C
Yield: 21 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 10.76 g (55 mmol) of N-chloromethylphthalimide. in 80 ml of DMF, 8.23 ml (55 mmol) of 1,8-diazabicyclo[5,4,0]-2-undecene was added. The mixture was stirred at room temperature for. 2 hours. After the solvent was distilled off, the reaction mixture was poured into water and extracted with ethyl acetate. The precipitate was filtered off. The aqueous layer was further extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.67 g of the desired compound (yield: 21%, colorless crystals). mp: 129.0°-131.0° C.
Reaction SMILES: [CH3:1][C:2]([C:5]([NH2:7])=[NH:6])([CH3:4])[CH3:3].Cl.[Cl:9][C:10](Cl)(Cl)[S:11]Cl.[OH-].[Na+]>ClCCl.O>[C:2]([C:5]1[N:7]=[C:10]([Cl:9])[S:11][N:6]=1)([CH3:4])([CH3:3])[CH3:1]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CC(C)(C)C(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)c1nsc(Cl)n1
Temperature: -15 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
6.83 g (50.00 mmol) of tert-butylcarbamidine hydrochloride are dissolved in 60 ml of dichloromethane and treated with 8.37 g (45.00 mmol) of trichloromethanesulphenyl chloride, before the reaction mixture is cooled to −15° C. A solution of 10.00 g (250 mmol) of sodium hydroxide in 20 ml of water is added dropwise and the mixture obtained is stirred at AT for 3 h. After adding 50 ml of dichloromethane, extracting three times with water and drying the combined organic phases over MgSO4, the solvent is evaporated under vacuum. (5.81 g, 90% purity, 60% yield, log P (pH 2.3)=3.44).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=1)=[O:26]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][S:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)(=[O:15])=[O:14])=[C:19]([C:25]([C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:26])[CH:20]=1
Reactant: Cc1ncoc1-c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(C(=O)c2cc(Cl)ccc2N)cn1
Product: Cc1ccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(-c3ocnc3C)cc2)cn1

Procedure:
The title compound was prepared according to the general procedure for the preparation of N-aryl-benzenesulfonamides using by the reaction of 4-(4-methyl-oxazol-5-yl)-benzenesulfonyl chloride with (2-amino-5-chloro-phenyl)-(6-methyl-pyridin-3-yl)-methanone and purified by HPLC: MS: m/z 468.0 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:41](=[O:42])[C:36]3=[C:37]([Cl:40])[C:38](=[O:39])[C:5]2=[C:6]([C:9]([C:11]([CH3:51])=[CH:12][C@H:13]([CH3:50])[C@@H:14]([OH:49])[C@@H:15]([CH3:48])[CH:16]=[CH:17][C@@H:18]([OH:47])[CH2:19][CH:20]=[C:21]([CH3:46])[C:22]([CH2:24][C@H:25]([OH:45])[C@@H:26]([CH3:44])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=[C:32](C)[C:33]([NH:35]3)=[O:34])=[O:23])=[O:10])[C:7]=1[OH:8].C(Cl)(Cl)Cl>CO>[CH3:44][C@@H:26]1[C@@H:25]([OH:45])[CH2:24][C:22](=[O:23])[C:21]([CH3:46])=[CH:20][CH2:19][C@H:18]([OH:47])[CH:17]=[CH:16][C@H:15]([CH3:48])[C@H:14]([OH:49])[C@@H:13]([CH3:50])[CH:12]=[C:11]([CH3:51])[C:9](=[O:10])[C:6]2[C:7]([OH:8])=[C:2]([CH3:1])[CH:3]=[C:4]3[C:41](=[O:42])[C:36](=[C:37]([Cl:40])[C:38]([C:5]=23)=[O:39])[NH:35][C:33](=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=[CH:27]1
Reactant: CC1=CC[C@H](O)C=C[C@H](C)[C@H](O)[C@@H](C)C=C(C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)C(C)=CC=CC=C[C@H](C)[C@@H](O)CC1=O)C3=O
Agent: C/C1=C/C=C\C=C\[C@H](C)[C@@H](O)CC(=O)/C(C)=C/C[C@H](O)/C=C/[C@H](C)[C@H](O)[C@@H](C)/C=C(\C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC1=O)C3=O
Agent: C/C1=C/C[C@H](O)/C=C\[C@H](C)[C@H](O)[C@@H](C)/C=C(/C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)/C=C\C=C/C=C\[C@H](C)[C@@H](O)CC1=O)C3=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC1=CC[C@H](O)C=C[C@H](C)[C@H](O)[C@@H](C)C=C(C)C(=O)c2c(O)c(C)cc3c2C(=O)C(Cl)=C(NC(=O)C=CC=CC=C[C@H](C)[C@@H](O)CC1=O)C3=O

Procedure:
36 g of crude extract were applied to a 3.5×49 cm silica gel column, and eluted successively with chloroform and a chloroform:methanol mixture in which the methanol concentration gradually rose to 5% (final composition 95:5). In this way, 14.6 g of semi-pure compound were obtained, and this was applied to a silica gel (200-300 mesh) column 6×31 cm in size, and was then eluted with a benzene:ethyl acetate mixture gradually increasing the ethyl acetate concentration to 60% (final composition 4:6). This resulted in fraction A in an amount of about 0.19 g and fraction B in an amount of about 1.2 g. For further purification, fraction A was applied to a 1.4×80 cm Sephadex LH 20® column and was eluted with methanol, resulting in 142 mg of a compound which was purified by preparative thin-layer chromatography (silica gel plates of thickness 0.5 mm) in a mixture of chloroform:methanol (95:5). This resulted in 96 mg of a pure compound which was identified as the known antibiotic naphthomycin A. Then a 6×30 cm silica gel H® column (without binder) was charged, as a chromatography column, with fraction B, and elution was carried out with a mixture of chloroform and methanol (96:4). This resulted in 650 mg of a semi-pure substance which was purified by a preparative thin-layer chromatography (silica gel plates 1 mm thick) in a mixture of chloroform and methanol (95:5), and was then recrystallized from a petroleum ether:benzene:ethyl acetate mixture, this resulting in naphthomycin H in an amount of 120 mg.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][NH:21][CH2:22][C:17]=4[O:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl.[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[CH3:24][N:25]([CH3:32])[CH2:26]/[CH:27]=[CH:28]/[C:29]([N:21]1[CH2:20][CH2:19][C:18]2[C:11]3[C:10]([NH:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=4)=[N:15][CH:14]=[N:13][C:12]=3[O:16][C:17]=2[CH2:22]1)=[O:30]
Reactant: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCNC4)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCN(C(=O)/C=C/CN(C)C)C4)c1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-ethynylphenyl)-5,6,7,8-tetrahydropyrido[4′,3′:4,5]furo[2,3-d]pyrimidin-4-amine from Example 43A (100 mg, 0.344 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (80 mg, 0.48 mmol) to yield 66 mg (46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Br[CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]2[NH:22][C:23](=[O:25])[O:24][C:20]=2[CH:19]=1>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)[CH2:11][CH2:10]1
Reactant: O=c1[nH]c2ccc(CCBr)cc2o1
Reactant: COc1ccccc1N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccccc1N1CCN(CCc2ccc3[nH]c(=O)oc3c2)CC1
Yield: 66.5 %

Procedure:
0.025 mol (4.82 g) of 1-(2-methoxyphenyl)-piperazine and 0.02 mol (4.85 g) of 6-(2-bromoethyl)-benzoxazolinone, dissolved beforehand in 50 cm3 of dioxane, were introduced into a 100 cm3 flask with a ground glass neck, fitted with a reflux condenser, and the mixture was then heated under reflux for 72 hours, with stirring. After cooling, filtration and drying, the precipitate formed was dissolved in a sufficient amount of a 3% aqueous solution of sodium hydroxide. A stream of carbon dioxide was then bubbled and the precipitate was filtered off, washed and dried. Recrystallisation from toluene gave 4.7 g of the title product having a melting point of 182°-184° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].Cl.[CH2:16]([O:18][C:19](=[O:30])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:30])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:25](=[O:29])[C@H:26]([CH3:28])[NH:27][C:12]([C:10]1[N:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[CH:8][CH:9]=1)=[O:14])[CH3:17]
Reactant: CCOC(=O)c1cccc(C(=O)O)n1
Reactant: CCOC(=O)[C@@H]1CCCN1C(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(C(=O)N[C@@H](C)C(=O)N2CCC[C@H]2C(=O)OCC)n1
Reaction time: 0.33 h
Yield: 49.6 %

Procedure:
To a stirred solution of 4.31 g (0.022 mol) of 6-ethoxycarbonyl-2-pyridinecarboxylic acid in 100 ml of anhydrous pyridine, there are added 5.5 g (0.022 mol) of L-alanyl-L-proline ethyl ester hydrochloride and 4.6 g of N,N'-dicyclohexyl carbodiimide. Stirring is continued for 20 minutes at room temperature, and the bulky precipitate of dicyclohexyl urea is filtered and washed with acetone. The solvent from the filtrate and washings is distilled off under reduced pressure and the crude product obtained is purified by column chromatography over silica gel using chloroform:acetone (10:1) as eluant. The isolated solid is crystallized from an acetone/isopropyl ether/petroleum ether mixture, to give 4.27 g of the desired product as acicular crystals (yield: 53%).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCc1ccccc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.1 %

Procedure:
Under an argon atmosphere, 225 g of 2-nitro-9,10-dihydrophenanthrene, 227 g of 2,3-dichloro-5,6-dicyano-p-benzoquinone, and 2.4 L of 1,4-dioxane were added, and then the mixture was stirred for 24 hours under heating reflux. After having been cooled to room temperature, the reaction solution was concentrated. The residue was purified by silica gel column chromatography, and was then washed with methanol. Thus, 134 g of a white crystal were obtained (in 60% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5]([OH:7])=O.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:7])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: C1COCCN1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCOCC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to morpholine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(morpholine-4-carbonyl)benzamide. MS (Q1) 456 (M)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C:16](=O)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:38](Br)([F:40])[F:39]>CN(C)C(=O)C>[C:4]([Si:1]([O:8][C@@H:9]1[CH2:10][O:11][C@@H:12]2[C:16](=[C:38]([F:40])[F:39])[CH2:15][O:14][C@H:13]12)([CH3:2])[CH3:3])([CH3:5])([CH3:6])[CH3:7]
Reactant: FC(F)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=O)CO[C@@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@@H]2C(=C(F)F)CO[C@@H]21

Procedure:
Alternatively, ketone (87) may be treated with triphenylphosphine and dibromodifluoromethane in N,N-dimethylacetamide to give tert-butyl((3R,3aS,6aR)-6-(difluoromethylene)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane (97) as detailed in Scheme 8.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:16])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOC(=O)c1ccc(Cl)cc1

Procedure:
To a solution of tert-butyl hydroxycarbamate (9.76 g, 73.3 mmol) in DCM (120 mL) at 0° C., is added 4-chlorobenzoyl chloride (8.13 mL, 73.3 mmol) followed by the dropwise addition of
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCCCCO)ccc21
Yield: 65.1 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (5-hydroxy-pentyl)-amide (59 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 5-amino-1-pentanol (21 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS m/z 495.0. 1H NMR (DMSO-d6, 400 MHz) δ 12.38 (bs, 1H), 8.53-8.33 (m, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.83-7.66 (m, 2H), 7.49 (d, 1H), 7.36 (d, 1H), 4.38 (s, 1H), 3.64 (s, 3H), 3.41 (q, 2H), 3.27 (q, 2H), 1.63-1.41 (m, 4H), 1.41-1.28 (m, 2H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]([NH2:20])=[O:19])=[N:14][C:13]=3[N:21]=2)=[CH:5][CH:4]=1)=O.[Cl-].[O:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:32][NH3+:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.CN(C=O)C.O>[O:29]=[C:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][CH2:32][NH:33][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][C:12]3[CH:17]=[N:16][C:15]([C:18]([NH2:20])=[O:19])=[N:14][C:13]=3[N:21]=2)=[CH:7][CH:8]=1
Reactant: [NH3+]CCC(=O)c1ccccc1
Reactant: NC(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: NC(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(CNCCC(=O)c4ccccc4)cc3)nc2n1
Reaction time: 0.5 h

Procedure:
A mixture of 7-(4-formylphenyl)-6-phenylpyrido[2,3-d]pyrimidine-2-carboxamide (2-6) (0.033 g, 0.093 mmol), 3-oxo-3-phenylpropan-1-aminium chloride (0.031 g, 0.168 mmol), and TEA (0.023 mL, 0.168 mmol) in 5% CH3COOH in DMF (0.5 mL) was stirred for 4 hr at which point NaBH(OAc)3 (0.039 g, 0.186 mmol) was added. The mixture was stirred for a 30 min. further. 2 drops of water were added and the material was purified by reverse phase HPLC. 1H-NMR (500 MHz, d6-DMSO) δ 9.90 (s, 1H), 8.88 (bs, 2H), 8.79 (s, 1H), 8.43 (s, 1H), 7.99 (d, 3H, J=7.3 Hz), 7.70 (t, 1H, J=7.1 Hz), 7.62-7.53 (m, 3H), 7.50 (d, 2H, J=8.3 Hz), 7.43-7.31 (m, 6H), 4.31-4.34 (m, 2H), 3.50 (t, 2H, J=6.6 Hz), 3.36-3.26 (m, 2H); LRMS, calc'd: 488.1; found 488.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]1([CH2:18][CH:19]=C)[CH2:9][C@H:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.C[OH:44]>>[CH3:1][O:2][C:3]([C@@:5]1([CH2:18][CH:19]=[O:44])[CH2:9][C@H:8]([F:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:4]
Reactant: CO
Reactant: C=CC[C@]1(C(=O)OC)C[C@H](F)CN1C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@@]1(CC=O)C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 5 h

Procedure:
1 g (3.5 mmol) (2R,4S)-2-allyl-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester is dissolved in 60 mL dichloromethane/methanol 1:1, cooled to −78° C., flushed with oxygen for two minutes then treated with a flux of ozone until the solution turns light blue. The solution is allowed to warm up to room temperature after addition of 1 g (1.1 eq.) triphenylphosphine, stirred an additional 5 h and column chromatographed (silica gel, TBME/petroleum ether 3:2) to yield 870 mg of the desired product as a clear oil.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][C:6](=[O:17])[CH2:7][CH2:8][C:9](=[O:16])[CH2:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[BH4-].[Na+].CC(C)=O>CO>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][CH2:10][CH:9]([OH:16])[CH2:8][CH2:7][CH:6]([OH:17])[CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:18]
Reactant: CN(C)CCCC(=O)CCC(=O)CCCN(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CN(C)CCCC(O)CCC(O)CCCN(C)C
Yield: 81.9 %

Procedure:
To a solution of 95 mg of 1,10-bis(dimethylamino)-4,7-decanedione in 3 ml of methanol was added 36 mg of sodium borohydride with ice-cooling, and the mixture was stirred for an hour, and after adding 5 ml of acetone, concentrated under a reduced pressure. After adding chloroform, the mixture was again concentrated under reduced pressure. After adding 5 ml of chloroform, the mixture was filtered to remove insoluble matter, concentrated under a reduced pressure, and further dried under a reduced pressure to obtain 79 mg of the title compound comprising Syn/Anti (1:1) mixture as a yellow oil.