Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([O:16][C:17]([C:19]1([C:50]([OH:52])=O)[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[N:36]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[C:39]([F:49])[CH:38]=4)[O:34][N:33]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN1CCOCC1.[NH2:60][N:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>O1CCCC1.O>[CH2:9]([O:16][C:17]([C:19]1([C:50](=[O:52])[NH:60][N:61]2[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]2)[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[N:36]=[C:35]([C:37]4[CH:42]=[CH:41][C:40]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[C:39]([F:49])[CH:38]=4)[O:34][N:33]=3)=[CH:30][CH:31]=2)[CH2:23][CH2:24]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NN1CCCCC1
Reactant: O=C(O)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: O=C(NN1CCCCC1)C1(C(=O)OCc2ccccc2)CCN(Cc2ccc(-c3noc(-c4ccc(-c5ccccc5)c(F)c4)n3)cc2)CC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
Isobutyl chloroformate (0.158 mL, 0.0012 mol) is added to a solution of 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-piperidine-4,4-dicarboxylic acid benzyl ester (0.6 g, 0.0010 mol) and N-methyl morpholine (0.156 mL, 0.0015 mol) in tetrahydrofuran (20 mL) at 5° C. The reaction mixture is stirred at 5° C. for 45 minutes. 1-Amino piperidine (0.162 mL, 0.0015 mol) is added to the reaction mixture and is stirred for 30 minutes at 5° C. and then at room temperature for 45 minutes. Demineralized water (10 mL) is added to the reaction mixture, Organic layer is separated and dried over sodium sulphate. Removal of solvent under reduced pressure gives a viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, hexane:ethyl acetate 70:30) to get 1-{4-[5-(2-fluoro-biphenyl-4-yl)-[1,2,4]oxadiazol-3-yl]-benzyl}-4-(piperidine-1-ylcarbamoyl)-piperidine-4-carboxylic acid benzyl ester.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19](=O)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:14][CH2:13]3)[C:7]=1[C:8]#[N:9].[OH2:29].[NH2:30][NH2:31].O>C(O)C>[CH3:27][C:23]1[CH:22]=[C:21]([CH2:20][C:19]([N:15]2[C:16]3[C:12](=[CH:11][C:10]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]5[NH:30][N:31]=[C:8]([NH2:9])[C:7]=45)=[CH:18][CH:17]=3)[CH2:13][CH2:14]2)=[O:29])[CH:26]=[CH:25][CH:24]=1
Reactant: O
Reactant: Cc1cccc(CC(=O)N2CCc3cc(-c4cncc(Cl)c4C#N)ccc32)c1
Reactant: NN
Solvent: CCO
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cncc5[nH]nc(N)c45)ccc32)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15.2 %

Procedure:
To 3-chloro-5-{1-[(3-methyl phenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-pyridinecarbonitrile (100 mg, 0.258 mmol) in Ethanol (6 mL) was added hydrazine monohydrate (1 mL, 31.9 mmol), and the reaction mixture was stirred at 80° C. overnight into a sealed vessel. LCMS analysis of the reaction mixture indicated the presence of starting material. Therefore, the reaction mixture was stirred at 100° C. overnight. The mixture was poured onto EtOAc and water. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The resulting residue was purified by flash chromatography on SiO2 (gradient: 100% Hexanes to 100% EtOAc to 20% CH3OH/EtOAc). The fractions containing the product were combined, concentrated, and triturated with Et2O to afford 4-{1-[(3-methyl phenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-c]pyridin-3-amine (15 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 3.25 (t, J=8.34 Hz, 2H), 3.85 (s, 2H), 4.24 (t, J=8.46 Hz, 2H), 4.6 (m, 1.3H(NH2)), 7.05-7.16 (m, 3H), 7.19-7.28 (m, 1H), 7.33 (d, J=8.34 Hz, 1H), 7.42 (s, 1H), 7.93 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.74 (s, 1H), 12.27 (br. s., 1H).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CC(=O)OCC.CN(C=O)C>[NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)[C@@H]1CCCN1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.0 g of Boc-Pro-OH, 7.4 g of H-Gly-OBzl, 3.0 ml of NEM and 3.1 g of HOBt are dissolved in 50 ml of EA with the addition of 5 ml of DMF. 4.8 g of DCC are added, and the mixture is left to stir at room temperature for 48 hours. After concentration in vacuo, the residue is dissolved in 50 ml of EA, and the solution is extracted by shaking twice with 30 ml of aqueous citric acid solution and twice with saturated aqueous sodium bicarbonate solution, and the organic phase is dried over sodium sulfate, filtered and evaporated. The residue is dissolved in 10 ml of trifluoroacetic acid, reaction is allowed to take place at room temperature for 1 hour, and the mixture is concentrated in vacuo. The residue crystallizes from EA/pentane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)[C:19]([Cl:35])=[CH:18][N:17]=1>>[Cl:35][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]2[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=2)=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][C:9](=[O:12])[N:8]([CH3:13])[CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: CN1Cc2cc(N)ccc2CCC1=O
Reactant: Cn1ccnc1-c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CN1Cc2cc(Nc3ncc(Cl)c(Nc4ccccc4-c4nccn4C)n3)ccc2CCC1=O

Procedure:
Following a procedure analogous to Example 1742a, 8-amino-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one and (2,5-dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine were converted to 8-{5-chloro-4-[2-(1-methyl-1H-imidazol-2-yl)-phenylamino]-pyrimidin-2-ylamino}-2-methyl-1,2,4,5-tetrahydro-benzo[c]azepin-3-one. TFA salt: 1H NMR (300 MHz, CDCl3) δ 10.87 (s, 1H), 8.63 (d, 1H), 8.14 (s, 1H), 7.50 (m, 4H), 7.35 (d, 2H), 7.29 (t, 1H), 7.17 (d, 1H), 7.11 (s, 2H), 4.53 (s, 2H), 3.87 (s, 3H), 3.22 (t, 2H), 3.11 (s, 3H), 3.01 (t, 2H); MS (m/e) 474 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH:3]=O.[NH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][C:19]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH:16]=2)[O:11][C:10]([CH3:30])([CH3:29])[CH:9]1[OH:31].[BH3-]C#N.[Na+].O>CO>[CH2:22]([NH:21][C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([CH3:29])([CH3:30])[CH:9]([OH:31])[CH:8]2[NH:7][CH2:1][C:2]([CH3:6])([CH3:5])[CH3:3])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)C=O
Reactant: CC1(C)Oc2ccc(CC(=O)NCc3ccccc3)cc2C(N)C1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CNC1c2cc(CC(=O)NCc3ccccc3)ccc2OC(C)(C)C1O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
4 ml of trimethylacetaldehyde was added to a solution of 11 g of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-benzylacetamide obtained above in 200 ml methanol. 2.44 g of NaBH3CN was added in several portions, and the resulting suspension was stirred for 2 hours at 50° C. After cooling to room temperature, the reaction mixture was poured into 200 ml water. The aqueous phase was extracted once with 150 ml EA, the combined organic phases were dried over sodium sulfate, and the solvent was largely evaporated at reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: ethyl acetate/cyclohexane 1:1 v/v) and drying of the product fractions on a rotary evaporator yielded 10.8 g N-benzyl-2-[3-hydroxy-2,2-dimethyl-4-(neopentylamino)-3,4-dihydro-2H-chromen-6-yl]acetamide as colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17]C=1.[CH:22]1[CH:27]=[CH:26]C=[CH:24][CH:23]=1>CCOCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:12]([O:11][CH:4]([O:3][CH2:1][C:2]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:15]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:13]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccccc1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(OCc1ccccc1)OCc1ccccc1
Yield: 99.5 %

Procedure:
To a 1000 mL round-bottomed flask was added ethyl 3,3-diethoxypropionate (20.0 g, 0.1051 mole), benzyl alcohol (22.7 g, 0.2102 mole), p-toluenesulfonic acid monohydrate (0.5 g, 0.0026 mole) and benzene (800 mL). The reaction can also be carried out in hexanes Heating the mixture at 80° C., the solvent was distilled from the reaction mixture in a 3.5 hour period monitored by 300 MHz NMR. The reaction can be carried out in hexanes. The resulting residue was dissolved in ether (@300 mL) and washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent removed in vacuo to give ethyl 3,3-dibenzyloxypropionate (9) as a colorless oil (32.9 g, 99.5% yield): 1H NMR (CDCl3) d 1.22 (t, 3H, J=7.2 Hz), 2.79 (d, 2H, J =5.9 Hz), 4.12 (q, 2H, J=7.2 Hz), 4.60 (d, 2H, J=11.6 Hz), 4.70 (d, 2H, J=11.6 Hz), 5.22 (t, 1H, J=6 Hz), 7.27-7.36 (m, 10H); IR (Neat) 3100, 3080, 3040, 2990, 2940, 2920, 2885, 1740, 1630, 1458, 1375, 1315, 1190, 1120, 1050, 1030, 740, 700. ##STR10##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+].O>C(O)C>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Reaction time: 1 h
Yield: 44.8 %

Procedure:
A stirred solution of d 6-amino-5-fluoro-1,3-dihydro-indol-2-one (2.26 g, 13.6 mmol) obtained from Example 6 in 40 ml of ethanol was added with 4-fluoro-benzaldehyde (1.5 ml, 13.6 mmol) at 0° C. in an ice-water bath. The resulting solution was stirred for 1 hour, added with sodium borohydride (1.08 g, 28.5 mmol) and heated to reflux overnight. The resulting mixture was added with water until a precipitate was formed. The solid was filtered and washed with water (50 ml×3). The crude was purified by silica gel column chromatography with dichloromethane and methanol (20:1) as eluents to give 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one (1.67 g, 45%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].I[C:20]1[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=1[CH:30]([CH3:32])[CH3:31]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:26]([CH3:29])(=[O:27])=[O:28])[CH:25]=[CH:20][C:21]=1[CH:30]([CH3:32])[CH3:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CC(C)c1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 2-iodo-1-isopropyl-4-(methylsulfonyl)benzene (Intermediate 91), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[S:17][C:10]=12.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:40])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and the reaction was allowed to stir for 30 minutes. The THF was removed under reduced pressure and the resultant product was purified by column chromatography on silica gel, eluent hexane/EtOAc (1:1), to afford the title compound 50 (35.4 mg, 53% yield). 1HNMR (DMSO) δ (ppm): 12.49 (s, 1H), 11.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1 Hz, 2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 (s, 3H) MS (m/z) 592.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22]([SH:23])[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37]>>[C:36]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][S:23][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:38])=[O:37]
Reactant: CCOC(=O)CCCCCBr
Reactant: SC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: O=C(O)CCCCCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-mercapto-6,11-dihydrodibenz[b,e]oxepine and ethyl 6-bromohexanoate were used and reacted in the same manner as in Example 24 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:27])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]=1[O:11][CH3:12])[C:5]([Cl:27])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1OC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1c(Cl)cc(C(=O)Cl)cc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 13 h

Procedure:
To 3-chloro-4-methoxy-5-trifluoromethoxybenzoic acid (401 mg), toluene (4 mL), N,N-dimethylformamide (1 droplet) and thionyl chloride (0.13 mL) were added, and then the mixture was stirred at 60° C. for 13 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (436 mg) as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([O:37]CC)=[O:36].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:34])[NH:20][C:21]3[S:22][C:23]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4nc5ccc(C(F)(F)F)cc5s4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 73.6 %

Procedure:
Ethyl 6-chloro-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylate (50 mg, 0.087 mmol) was diluted with THF (500 μL) followed by the addition of aqueous NaOH (433 μL, 0.43 mmol) and ethanol (100 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 0.5N aqueous HCl. The layers were separated and the organic layer was concentrated to yield 6-chloro-7-(4-(6-(trifluoromethyl)benzo[d]thiazol-2-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (35 mg, 0.064 mmol, 74% yield). MS (apci, positive) m/z=548.8. 1H NMR (400 MHz, D6 DMSO) δ 13.06 (br s, 1H), 8.54 (s, 1H), 8.19 (d, 2H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.49 (s, 1H), 7.06 (d, 2H), 6.76 (s, 1H), 4.30-4.26 (m, 1H), 4.10 (dt, 1H), 3.86 (t, 1H), 2.26-2.20 (m, 1H), 2.11-2.02 (m, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C=[C:10]1O[C:12](=[O:13])[CH2:11]1.[C:15](O)(=O)C>>[O:13]=[C:12]1[CH:11]=[CH:10][C:4]2[C:3](=[CH:2][C:1]([NH2:8])=[CH:6][CH:5]=2)[N:7]1[CH3:15]
Reactant: Nc1cccc(N)c1
Reactant: C=C1CC(=O)O1
Reactant: CC(=O)O
Product: Cn1c(=O)ccc2ccc(N)cc21
Yield: 70.7 %

Procedure:
43.2 gm. of at least 98 percent pure 1,3-phenylene diamine (melting point: 60° to 62° C) and 100 ml of 10 percent acetic acid are placed in a sulfurizing flask equipped with an anchor bolt, reflux cooler, dripping funnel, thermometer and water bath. 35.2 gm. of diketene were allowed to drip into the reaction mixture over the course of about 20 minutes at room temperature. The reaction mixture was stirred during the addition. The temperature was allowed to rise with the aid of the reaction heat to 60° to 65° C. After completion of the addition of diketene, the reaction was allowed to continue for another hour at 60° to 65° C. After cooling to about 15° C. the resultant precipitate was separated out and dried under vacuum at 60° to 70° C until the precipitate reached a constant weight. 49.2 gm. of yellow, discolored 1,2-dihydro-2-oxo-1-methyl-7-amino-quinoline with a melting point of 268° to 269° C were obtained, which corresponded to a yield of 70.7 percent, based on the m-phenylene diamine. After a single recrystallization from dimethylformamide/H2O (1:1), the product was colorless and had a melting point of 274.6° to 275.4°C.
Reaction SMILES: [CH2:1]([N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8])[CH2:2]CC=C.C[N+]1([O-])CC[O:23]CC1.S([O-])([O-])=O.[Na+].[Na+].[CH3:33][C:34]([CH3:36])=[O:35]>O>[OH:35][CH:34]([CH2:36][OH:23])[CH2:33][CH2:2][CH2:1][N:6]1[C:15](=[O:16])[C:14]2[N:13]([CH3:17])[CH:12]=[N:11][C:10]=2[N:9]([CH3:18])[C:7]1=[O:8]
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C=CCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cn1cnc2c1c(=O)n(CCCC(O)CO)c(=O)n2C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A solution of 1-(4-pentenyl)-3,7-dimethylxanthine (2.48 g, 10 mmol), 4-methylmorpholine-N-oxide (1.49 g, 12.7 mmol) and potassium osmate dihydrate (7.3 mg; 0.02 mmol) in acetone (20 mL) and water (5 mL) was stirred for 6 hours. A solution of 20% aqueous sodium sulphite (10 ml) was added and stirred for 30 minutes. The reaction mixture was extracted with 25% ethanol/dichloromethane (4×250 mL). The combined organic extracts were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using ethyl acetate eluant to yield 2.5 g (88% yield) of 1-(4,5-dihydroxypentyl)-3,7-dimethylxanthine (inventive compound no. 1584).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]1[NH:19][C:20]([NH:22][C:23]([O:25][CH3:26])=[O:24])=[S:21].[OH-].[Ca+2].[OH-].[CH3:30]OS(OC)(=O)=O>CN(C)C=O.O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:3]1[NH:19][C:20](=[N:22][C:23]([O:25][CH3:26])=[O:24])[S:21][CH3:30]
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1=C(Cc2ccccc2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSC1=C(Cc2ccccc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-iminophenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.88 g.; 0.01 mol) in dimethylformamide (40 ml.) and water (10 ml.) there is added calcium hydroxide (0.74 g.; 0.01 mol). The mixture is stirred at room temperature for four hours and to it there is added dimethylsulfate (1.26 g.). The mixture is stirred at room temperature for four hours and the precipitate collected and dried to afford 1-iminophenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:14]1)[C:5]([O:7]C)=[O:6].[Li+].[OH-].C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CO>[I:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]1[CH2:17][CH2:16][N:15]([C:18]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])[CH2:14]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
A mixture of compound 34d (180 mg, 0.41 mmol), LiOH (39 mg, 1.62 mmol), THF (3 mL), MeOH (3 mL), and H2O (3 mL) was stirred at room temperature for 4 h. The mixture was acidified with 15% aqueous citric acid and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resultant residue was dried under reduced pressure for 2 h to give compound 34e (166 mg).
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[S:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1.C1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Reactant: c1ccsc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccsc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 80.3 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (150 mg, 0.39 mmol, prepared in example 1), thiophene-3-benzene boronic acid (74 mg, 0.56 mmol), potassium carbonate (80 mg, 0.56 mmol) and tetrakis(triphenyl phosphine)palladium(0) (31 mg, 0.027 mmol) were combined in dioxane/water (15 mL, 3:1). The mixture was heated at 100° C. under stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated and washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (236 mg) as a dark oil. The resulting oil was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of hexane/ethyl acetate 7:3 to yield the title compound (107 mg, 81%) as a white solid. Ion spray M.S. 340.0 (M*−1).