Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[CH2:16][CH2:17][CH:18]1[O:22][C:21](=[O:23])[N:20]([CH3:24])[CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C(OC(C)C)(C)C.CC(O)C>C(O)CCC>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH:18]2[O:22][C:21](=[O:23])[N:20]([CH3:24])[CH2:19]2)[CH2:13][CH2:14]1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: CCCCO
Product: Cc1cccc(C)c1N1CCN(CCC2CN(C)C(=O)O2)CC1
Yield: 56.7 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.8 g (0.02 mol) of 1-(2,6-dimethylphenyl)piperazine (Emka-Chemie), 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 mL of 1-butanol gave 3.6 g (57%) of white solid, mp 107°-108° C. (isopropyl ether/2-propanol).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:12]=3[NH:11][C:10]2=[O:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=2[CH2:34][CH2:33][C:32]2[CH:42]=[C:43]([F:46])[CH:44]=[CH:45][C:31]1=2.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:41][C:39]1[CH:38]=[CH:37][C:36]2[C:30](=[CH:29][C:16]3[CH:15]=[CH:14][C:13]4[N:9]([CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[C:10](=[O:27])[NH:11][C:12]=4[CH:17]=3)[C:31]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:32]=3[CH2:33][CH2:34][C:35]=2[CH:40]=1
Reactant: Fc1ccc2c(c1)CCc1cc(F)ccc1C2=CBr
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c(=O)n3CCN2CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=c1[nH]c2cc(C=C3c4ccc(F)cc4CCc4cc(F)ccc43)ccc2n1CCN1CCOCC1
Yield: 45.4 %

Procedure:
Following procedures essentially as described in Example 219, mix 1-(2-morpholin-4yl-ethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (520 mg, 1.4 mmol), 5-bromomethylene-2,8-difluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (510 mg, 1.6 mmol)(prepared using a procedure essentially as described for the 2,8-dichloro derivative in Example 182), 2N Na2CO3 (1 mL), dioxane (10 mL) and (Ph3P)4Pd (67 mg, 0.06 mmol). Purify the crude product by column chromatography using MeOH/ethyl acetate to give 310 mg colorless oil that solidified upon drying, HPLC (ISO80-10M) t=2.03 (97%). MS (ES) 488 (M+1), 486 (M−1). H NMR 10.69 (s, 1H), 7.49 (dd, 1H, J=8.4, 6.2 Hz), 7.22 (dd, 1H, J=9.7, 2.2 Hz), 7.02 (td, 1H, J=12.0, 4.2 Hz), 6.97-6.83 (m, 4H), 6.81 (s, 1H), 6.72 (d, 1H, J=7.9 Hz), 6.56 (s, 1H), 3.80 (t, 2H, J=6.2 Hz), 3.47 (t, 4H, J=4.2 Hz), 3.31 (s, 2H), 2.90 (s, 2H), 2.48 (m, 2H), 2.38 (s, 4H).
Reaction SMILES: [O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([C@H:9]([CH3:11])[OH:10])[OH:8])[OH:6])[OH:4].C(O)[C@H]([C@@H]([C@@H]([C@H](C)O)O)O)O.C(O)C(N)(CO)CO.Cl>>[CH3:11][C:9]([C@H:7]([C@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])=[O:10]
Reactant: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Agent: NC(CO)(CO)CO
Product: CC(=O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
L-Fucose (6-deoxy L-galactose) was reduced, for a microbial oxidation of the resulting L-fucitol (6-deoxy L-galactitol) with E. agglomerans 221e [the bacterial cell at OD600=30, Tris-HCl buffer (pH 8.0) of 50 mM, the substrate 6-deoxy L-galactitol at 1%] at 30° C. for 6 hours. Only 1-deoxy D-tagatose was produced. FIG. 44(a) shows the reaction mixture after reaction, while FIG. 44 (b) shows the results of HPLC analysis of the produced 1-deoxy D-tagatose. The optical rotation was +14.0. 13C NMR spectrum thereof is shown in FIG. 45.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[NH:16][CH2:15][CH2:14]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[CH2:13]1[C@H:22]2[C@H:17]([CH2:18][CH2:19][C:20]3[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=32)[N:16]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([OH:1])[CH:3]=2)=[O:7])[CH2:15][CH2:14]1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: COc1ccc(C(=O)O)cc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1O
Yield: 42 %

Procedure:
The title compound is prepared from 3-hydroxy-4-methoxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 42% of theory; LC (method 4): tR=1.93 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([S:8](=[O:11])(=[O:10])[NH2:9])=[C:5]([C:12]([OH:14])=O)[CH:4]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[O:7][C:6]2[S:8](=[O:11])(=[O:10])[NH:9][C:12](=[O:14])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)O)c(S(N)(=O)=O)o1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc2c(o1)S(=O)(=O)NC2=O
Yield: 45.4 %

Procedure:
5.0 gm (0.023 mol) of 5-ethyl-2-sulfamoyl-furan-3-carboxylic acid were admixed with 4.75 gm (0.023 mol of phosphorus pentachloride in 300 ml of anhydrous toluene, and the mixture was refluxed for 8 hours. After filtering, the filtrate was evaporated in vacuo and the residue was recrystallized from carbon tetrachloride, yielding 2.1 gm (46% of theory) of 5-ethyl-furo[3,2-d]isothiazole-3(2H)-one-1,1-dioxide.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[N:21]2)=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ICCCCc1ccc(OCc2ccccc2)cc1
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCCn3ccnn3)cc2)cc1
Temperature: 70 °C
Reaction time: 26.5 h
Yield: 42.4 %

Procedure:
Benzyl 4-(4-iodobutyl)phenyl ether (1.1 g), 1H-1,2,3-triazole (0.31 g), and potassium carbonate (0.622 g) were suspended in DMF (7.5 ml), followed by stirring at 70° C. for 26.5 hours. After cooling, the reaction mixture was extracted with ethyl acetate and washed with water and saturated saline. Under reduced pressure, the solvent was distilled off; the residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:3) to yield the titled compound (0.391 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[CH:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[CH3:20][N:21]1[CH:25]=[N:24][C:23]([CH2:26][OH:27])=[N:22]1>>[CH3:20][N:21]1[CH:25]=[N:24][C:23]([CH2:26][O:27][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[CH:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)=[N:22]1
Reactant: Cn1cnc(CO)n1
Reactant: Clc1nn2c(-c3ccon3)ncc2c2ccccc12
Product: Cn1cnc(COc2nn3c(-c4ccon4)ncc3c3ccccc23)n1

Procedure:
The title compound was prepared from 6-chloro-3-(isoxazol-3-yl)-imidazo[5,1-a]phthalazine (Part b) and (2-methyl-1,2,4-triazol-5-yl)methanol as described in Example 1, Part c. 1H NMR (360 MHz, CDCl3) δ 3.96 (s, 3H), 5.7 (s, 2H), 7.40 (s, 1H), 7.52 (t, J=8 Hz, 1H), 7.76 (t, J=8 Hz, 1H), 7.89 (s, 1H), 8.0 (d, J=8 Hz, 1H), 8.17 (d, J=8 Hz, 1H), 8.56 (s, 1H). MS (ES+) m/e 348 [MH]+.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[C:9]([N+:13]([O-])=O)=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:16])[NH:5][CH2:4][CH2:3]1>CO.[Pd]>[NH2:13][C:9]1[C:8]2[N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:16])[C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: CN1CCNC(=O)c2cccc(N)c21
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
1-Methyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (#) (100 mg, 0.45 mmol) was dissolved in MeOH (20 ml) and placed in a Parr bottle. Pd—C (10%, 10 mg) was added, and the resulting mixture was shaken under 20 psi H2 for 1.5 h. The reaction mixture was filtered through celite, washed with MeOH, and concentrated to afford 9-Amino-1-methyl-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as a brown solid (86 mg, 99%). mp 130-133° C.; LCMS: m/z=192.30 (M+H+); 1H NMR (400 MHz, CDCl3) δ 7.26 (m, 1H), 6.80 (m, 2H), 3.79 (bs, 2H), 3.45 (m, 4H), 3.16 (s, 3H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:29])([CH3:28])[C@@H:14]([O:20]CC1C=CC=CC=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:10])=[O:9])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][S:8]([O:11][CH2:12][C:13]([CH3:28])([CH3:29])[C@@H:14]([OH:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](O)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Following the general procedure for the hydrogenolysis of benzyl ethers of Description 18, a mixture of ethyl (2R)-4-{[3-(acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(phenylmethoxy)butanoate acid (22b) (0.8 g, 1.8 mmol) and 700 mg palladium (10 wt. % on activated carbon) in 20 mL of ethanol (EtOH) was stirred overnight under a hydrogen atmosphere. After purification by mass-guided preparative HPLC, 380 mg (61% yield) of the title compound (22) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=0.96 (s, 3H), 1.13 (s, 3H), 1.34 (t, J=7.2 Hz, 3H), 1.99 (s, 3H), 2.04-2.12 (m, 2H), 3.12-3.26 (m, 2H), 3.32 (d, J=6.0 Hz, 1H), 3.34-3.47 (m, 2H), 3.97 (d, J=8.8 Hz, 1H), 4.03 (d, J=6.0 Hz, 1H), 4.16 (d, J=9.6 Hz, 1H), 4.23-4.26 (m, 2H), 6.00-6.06 (br. m, 1H) ppm. MS (ESI) m/z: 339.95 (M+H)+, 337.94 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([CH3:16])=[C:9]([CH3:17])[C:8]=1[N+:18]([O-:20])=[O:19])[CH2:4][CH3:5])[CH3:2].C(O)C.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O>[CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:17])[C:10]([CH3:16])=[CH:11][C:12]=1[NH2:13])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: CCC(CC)Nc1c(N)cc(C)c(C)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 3 h

Procedure:
N-(1-Ethylpropyl)-2,6-dinitro-3,4-xylidine (100 g.) is dissolved in 2500 ml. of ethanol and a solution of sodium sulfide nonahydrate (240 g.) and sodium bicarbonate (84 g.) in 500 ml. of water is added at 25°-42° C. The mixture is heated to 65° C. and held at 60°-65° C. for 3 hours. The mixture is then poured into water and extracted 3 times with 1 liter portion of ether. The ether extracts are combined and dried over magnesium sulfate. Removal of the drying agent and solvent leaves a dark solid which is recrystallized 3 times from hexane and then 3 times from hexane-ethanol. The product (35.0 g.), an orange solid, has m.p. 80°-82° C. Analysis Calcd. for C13H21N3O2 : C, 62.12; H, 8.41; N, 16.71. Found: C, 62.41; H, 8.33; N, 16.47.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[O:21])[CH:6]([C:19]#[N:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])C.C([OH:25])C.O>CS(O)(=O)=O>[OH:21][C:5]1[C:4](=[O:3])[NH:20][C:19](=[O:25])[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCO
Reactant: CCCCCCCCCCCCC(C#N)C(=O)C(=O)OCC
Agent: CS(=O)(=O)O
Solvent: O
Product: CCCCCCCCCCCCC1=C(O)C(=O)NC1=O
Reaction time: 8 h

Procedure:
1 G. of the 3-cyano-2-oxopentadecanoic acid ethyl ester is dissolved in 5 ml of methanesulfonic acid and the mixture allowed to stand overnight at room temperature. The reaction mixture is worked up by first pouring into ethanol-water (20 ml ethanol--5 ml water). After standing for several hours, the ethanol is removed by evaporation. The aqueous acidic residue is diluted further with water and then extracted with chloroform. The chloroform solution is then washed well with water, dried and evaporated to give the desired 3-hydroxy-4-(n-dodecyl)-3-pyrroline-2,5-dione. Recrystallization from hexane or cyclohexane provides pure 3-hydroxy-4-(n-dodecyl)-3-pyrroline-2,5-dione, mp 108°-109° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[N+:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)([O-:29])=[O:28]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:27]([O-:29])=[O:28])[CH:35]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc([N+](=O)[O-])c2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-nitrobenzene-boronic acid in analogy to Example 2b): MS (ISN): 499.1 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[Cl:11]N1C(=O)CCC1=O.O.C(Cl)Cl>C(O)(=O)C>[Br:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(Br)ccc1Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Br)c(Cl)cc1Cl
Yield: 99.5 %

Procedure:
1 g of 5-bromo 2-chloro anisole and 0.66 g of N-chloro succinimide in 10 ml of acetic acid is heated at 90° C. for 20 hours. The reaction medium is poured into water, extraction is carried out with methylene chloride. The organic phase is washed with a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulphate and evaporated under reduced pressure. 1.15 g of sought product is obtained.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.Cl>O>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCNC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 600g 2-chloro-5-nitrobenzoic acid, 900g methyltetradecylamine (84%, tertiary amines as impurities) and 500 ml triethylamine was heated on a steam bath for 7 hours and then poured into 2 liters of water and made acid with HCl. The reaction product was filtered, air dried and then recrystallized from methanol and then from petroleum ether. Yield: 820g, m.p. = 100°-101°.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)([OH:13])[CH2:9][CH2:8]1.[F:21][C:22]1[CH:23]=[C:24]([C@@H:29]2[C:34]([C:35](O)=[O:36])=[C:33]([CH3:38])[NH:32][C:31](=[O:39])[NH:30]2)[CH:25]=[CH:26][C:27]=1[F:28].FC1C=C([C@@H]2C(C(O)=O)=C(COC)NC(=O)N2)C=CC=1F>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:10]2([OH:13])[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:35]([C:34]3[C@@H:29]([C:24]4[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=4)[NH:30][C:31](=[O:39])[NH:32][C:33]=3[CH3:38])=[O:36])[CH2:12][CH2:11]2)=[CH:19][CH:18]=1
Reactant: NCCCN1CCC(O)(c2ccc(F)cc2)CC1
Reactant: CC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: COCC1=C(C(=O)O)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1
Agent: Cl
Product: CC1=C(C(=O)NCCCN2CCC(O)(c3ccc(F)cc3)CC2)[C@@H](c2ccc(F)c(F)c2)NC(=O)N1

Procedure:
1-(3-Amino-propyl)-4-(4-fluorophenyl)-piperidine-4-ol dihydrochloride was used in place of 2-(1-(3-Amino-propyl)-piperidine-4-yl]-5-fluoro-benzonitrile dihydrochloride and (4R)-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid was used go in place of (4R)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[CH:33]=[C:34]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:35]=[CH:36][CH:37]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:30]([OH:31])=[O:29])[CH:33]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccccc2CSCCOc2ccccc2)c1
Yield: 100 %

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid ethyl ester (3.65 g, 9.30 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.67 g, 27.9 mmol, 3 eq.). When complete, the reaction was worked up as described leaving 2′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3.39 g, 100% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([S:22][CH3:23])=[N:6][C:7]=1[C:8]([NH:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[S:13])=O>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([C:8]2[S:13][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[N:11][N:10]=2)=[N:6][C:5]([S:22][CH3:23])=[N:4][CH:3]=1
Reactant: CSc1ncc(Cl)c(C(=O)NNC(=S)Nc2ccc(F)cc2)n1
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1ncc(Cl)c(-c2nnc(Nc3ccc(F)cc3)s2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.3 %

Procedure:
1-(5-Chloro-2-(methylthio)pyrimidine-6-carbonyl)-4-(4-fluorophenyl)thiosemicarbazide (1.08 g, 2.9 mmol) was diluted in 60 mL sulfuric acid. This solution was stirred at room temperature for 5 min before cooling in an ice bath. The reaction mixture was carefully diluted with excess H2O forming the product as a bright orange ppt. The product was collected by filtration and dried in a vacuum oven overnight to give 0.721 g (71% yield) of product as a bright orange solid. MS (M+H)+ 354.
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[OH:23][C:24]([CH3:29])([CH3:28])[C:25](O)=[O:26].C(N(CC)C(C)C)(C)C.[Br:39][C:40]1[C:49]([CH3:50])=[CH:48][C:43]([C:44]([NH:46]O)=[NH:45])=[CH:42][C:41]=1[CH3:51]>CN(C)C=O.O>[Br:39][C:40]1[C:49]([CH3:50])=[CH:48][C:43]([C:44]2[N:45]=[C:25]([C:24]([OH:23])([CH3:29])[CH3:28])[O:26][N:46]=2)=[CH:42][C:41]=1[CH3:51]
Reactant: Cc1cc(C(=N)NO)cc(C)c1Br
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2noc(C(C)(C)O)n2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU; 0.55 g) is added to a solution of 2-hydroxy-isobutyric acid (0.18 g) and N,N-diisopropyl-ethylamine (1.4 mL) in N,N-dimethylformamide (5 mL) at room temperature. The solution is stirred at room temperature for 10 min prior to the addition of 4-bromo-N-hydroxy-3,5-dimethyl-benzamidine (0.40 g). The solution is stirred at room temperature for another 10 min and then at 110° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extract is washed with brine, dried (MgSO4), and concentrated. The residue is chromatographed on reversed phase (HPLC; acetonitrile/water/trifluoroacetic acid) to give the title compound. LC (method 11): tR=1.16 min; Mass spectrum (ESI+): m/z=313/315 (Br) [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[C:22](=O)(O)[O-:23].[Na+].C(Cl)(Cl)=O>C(Cl)Cl>[N:21]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][N:16]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:2]([CH3:1])[CH:3]=1)=[C:22]=[O:23]
Reactant: Cc1cc(N)ccc1Oc1ncccc1-c1ccncn1
Reactant: O=C([O-])O
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N=C=O)ccc1Oc1ncccc1-c1ccncn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3-methyl-4-(3-(pyrimidin-4-yl)pyridin-2-yloxy)benzenamine (93 mg, 0.33 mmol) in CH2Cl2 (8 mL) was added saturated sodium bicarbonate (4 mL) followed 5 minutes later by phosgene (20% solution in toluene, 0.27 mL, 0.50 mmol). The mixture was stirred for 15 minutes at RT, diluted with CH2Cl2 and extracted with water. The organic layer was dried over sodium sulfate, filtered, concentrated and used without purification.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:32]=[O:33])(=[O:3])[CH3:2].O.P([O-])(O)(O)=[O:36].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:32]([OH:36])=[O:33])(=[O:3])[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCCOC(C)=O)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 21.4 %

Procedure:
To a stirred solution of 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carbaldehyde (60 mg, 0.13 mmol) in t-butanol (0.5 mL) and water (0.5 mL) solution was added sodium dihydrogenphosphate monohydrate (73 mg, 0.53 mmol), 2-methyl-2-butene (0.090 mL, 0.80 mmol) and sodium chlorite (72.2 mg, 0.80 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 6-(3-acetoxy-propoxy)-1-(3-ethoxy-benzoyl)-7-methoxy-isoquinoline-4-carboxylic acid (13 mg, 21% yield) as a yellow solid. HR-MS m/e calcd for C25H25N1O8 (M−H+) 468.1653, found 468.1657; 1H NMR (300 MHz) compatible.