Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12].Br[CH2:14][CH2:15][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(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:29]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[O:11][CH3:12])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: COc1cc2cc[nH]c2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOc1cc2[nH]ccc2cc1OC
Temperature: 80 °C
Yield: 35 %

Procedure:
6-Hydroxy-5-methoxyindole (2 g; 0.0123 mole) dissolved in 10 ml of dimethylformamide (DMF) is introduced dropwise in the course of 20 minutes into a mixture of 1-bromohexadecane (4.5 g; 0.0148 mole) and potassium carbonate (1.87 g; 0.0135 mole) in 45 ml of DMF at 70° C. and under nitrogen. The reaction mixture is stirred under nitrogen at 80° C. for 3 and a half hours. The blackish mixture is poured into ice-cold water with stirring and the brownish solid formed is immediately filtered off and washed with water. It is taken up in dichloromethane and dried over sodium sulphate. After chromatography on silica 60 (eluent: toluene/CH2Cl2, 50:50), and recrystallization in hexane, the derivative 26 is obtained (1.66 g; 35% yield).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 3 h
Yield: 102.8 %

Procedure:
A mixture of tert-butyl {2-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]ethyl}carbamate 42 (0.21 g, 0.48 mmol) and Pd/C (0.063 g) in methanol (10 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through celite pad and concentrated to provide 43 (0.17 g. quant. yield) as a light yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CC(O)c2ccc(F)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: CS(=O)(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.2 %

Procedure:
To a cold (0° C.) solution of the product of step 2 (5.45 g, 18.5 mmol) in CH2C2 (350 mL) was added PCC (6.13 g, 28 mmol). The mixture was stirred at r.t. for 6.5 h and filtered through a short pad of silica gel (eluted with acetone). The eluant was concentrated and the residue was chromatographed on silica gel (eluted with 30 % EtOAc/CH2Cl2) to give 5.2 g of the title compound.
Reaction SMILES: NC[C@@H]1OC(=O)N(C2C=CC(S(C)=O)=C(F)C=2)C1.[N:19]([CH2:22][C@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH3:38])=[O:36])=[C:31]([F:39])[CH:30]=2)[CH2:24]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[NH2:19][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH2:37][CH3:38])=[O:36])=[C:31]([F:39])[CH:30]=2)[CH2:24]1
Reactant: CCS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: CS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCS(=O)c1ccc(N2C[C@H](CN)OC2=O)cc1F

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-aminomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-ethylsulfinyl-3′-fluorophenyl]oxazolidine-2-one (0.235 g, 0.752 mmol) and triphenylphosphine (0.207 g, 0.790 mmol). Yield 0.177 g (82%). MS (m/z): [M+H]+=287.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Br[C:17]1C2N(CCO)C=NC=2C=CC=1>>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6]([C:7]#[N:8])=[CH:9][CH:10]=[CH:11][C:12]=2[N:13]=[CH:17]1
Reactant: OCCn1cnc2cccc(Br)c21
Reactant: N#Cc1cccc([N+](=O)[O-])c1NCCO
Product: N#Cc1cccc2ncn(CCO)c12

Procedure:
1-(2-Hydroxyethyl)-1H-benzimidazole-7-carbonitrile was prepared in two steps starting from 2-[(2-hydroxyethyl)amino]-3-nitrobenzonitrile (0.99 g) according to the procedure described for the synthesis of 2-(7-bromo-1H-benzimidazol-1-yl)ethanol. Yield 0.49 g (55 %). MS (ESI) m/z 188.1 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm: 3.81 (q, J=5.1 Hz, 2H), 4.53 (t, J=5.3 Hz, 2H), 5.03 (t, J=5.1 Hz, 1H) 7.36 (t, J=7.8 Hz, 1H), 7.76 (dd, J=7.6, 1.0 Hz, 1H), 8.04 (dd, J=8.1, 1.0 Hz, 1H), 8.37 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15]C(OC)=O)=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=2[C:21]1=[O:30].Cl>CO>[F:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([OH:15])=[CH:10][C:9]=1[N:20]1[C:24](=[O:25])[C:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C:22]=2[C:21]1=[O:30]
Reactant: COC(=O)Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)c(Cl)cc1F
Reaction time: 5 h

Procedure:
Potassium carbonate (4.6 g, 33.3 mmol) was added to a solution of N-(2-fluoro-4-chloro-5-methoxycarbonyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (11.8 g, 33.4 mmol) obtained as described above in methanol (100 ml), followed by stirring for 5 hours under refluxing. After completion of the reaction, the mixture was poured into 1N hydrochloric acid (200 ml), and the mixture was extracted with ethyl acetate (100 ml×3 times). The organic layer was washed with water, dried, and the solvent was distilled off under reduced pressure to obtain a crude product (9.4 g). The product was recrystallized from ether/hexane to obtain N-(2-fluoro-4-chloro-5-hydroxypheyl)-3,4,5,6-tetrahydrophthalimide as a white solid (6.7 g, 22.7 mmol, 67.8.% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:18])=[C:7]([F:17])[CH:8]=2)[N:3]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:11]1[C:2]([N:20]([CH3:19])[CH2:21][CH2:22][C:23]#[N:24])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([F:17])=[C:6]([F:18])[CH:5]=2)=[O:13])[CH3:16]
Reactant: CNCCC#N
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC#N
Temperature: 20 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of 16.3 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline prepared as described in Example 1 and 10 g of N-methyl-N-β-cyanoethylamine in 160 cm3 of toluene are added 19.08 g of sodium carbonate. The suspension obtained is heated at reflux and then stirred for 4 hours at this temperature. The reaction mixture is subsequently cooled to approximately 20° C., followed by washing with 3 times 50 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2-(N-methyl-N-β-cyanoethylamino)quinoline are obtained in the form of an oil, which is used without further purification for the subsequent steps.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7](=[O:13])[NH:8][C:9](=[O:12])[C:10]=2[N:11]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][CH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7](=[O:13])[NH:8][C:9](=[O:12])[C:10]=2[N:11]=1)(=[O:16])[CH3:15]
Reactant: Cc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Reactant: CC(=O)O
Product: CC(=O)OCc1ccc2[nH]c(=O)[nH]c(=O)c2n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 5000-mL 4-necked round-bottom flask was placed a solution of 6-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione 2 (120 g, 677.97 mmol, 1.00 equiv) in acetic acid (2400 mL). This was followed by the addition of m-CBPA (608 g, 3.51 mol, 5.18 equiv) in several batches. The resulting solution was stirred overnight at 100° C. The resulting mixture was cooled and concentrated under vacuum. The residue was washed with 2×1500 mL of ether and 2×500 mL of DCM, then it was dissolved in HOAc (1200 mL) and acetic anhydride (500 mL). The resulting solution was stirred for 0.5 h at 110° C. The reaction mixture was cooled and filtered. The filtrate was concentrated under vacuum. The residue was washed with 2×500 ml of ether and dried. This resulted in 80 g (50%) of (2,4-dioxo-1,2,3,4-tetrahydropyrido[3,2-d]pyrimidin-6-yl)methyl acetate 3 as a brown solid.
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[F:15][C:16]([F:57])([F:56])[C:17]1[CH:18]=[C:19]([NH:27][C:28](=[O:55])[NH:29][C:30]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:31]=2[O:32][C:33]2[CH:41]=[CH:40][C:39]([C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[CH:38][C:34]=2[C:35]([O-:37])=[O:36])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1>C(OCC)(=O)C.[Pd]>[F:15][C:16]([F:56])([F:57])[C:17]1[CH:18]=[C:19]([NH:27][C:28](=[O:55])[NH:29][C:30]2[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:31]=2[O:32][C:33]2[CH:41]=[CH:40][C:39]([C:42]([CH3:45])([CH3:46])[CH2:43][CH3:44])=[CH:38][C:34]=2[C:35]([OH:37])=[O:36])[CH:20]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:22]=1
Reactant: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)[O-])c1
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(Oc2ccc(C(F)(F)F)cc2NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(C(=O)O)c1
Reaction time: 16 h

Procedure:
Benzhydrol-2-[2-[3-[3,5-bis(trifluoromethyl)phenyl]ureido]-4-trifluoromethylphenoxy]-5-(1,1-dimethylpropyl)benzoate (110 mg, 0.0002 mol) was dissolved in ethyl acetate and a palladium on carbon catalyst (50 mg) was added, under argon. The mixture was hydrogenated in a parr bottle at 54 psi, for 16 h. The mixture was filtered through Celite® and washed with ethyl acetate and methanol. The solvents were evaporated and the residue was flash chromatographed (silica gel, ethyl acetate/hexane/formic acid) to yield the tide compound; mp 238°-240° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:16]([NH:19][C:20]([NH2:22])=[S:21])(=[O:18])[CH3:17]>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[N:22][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Reactant: CC(=O)NC(N)=S
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1

Procedure:
This material is prepared from 1-(3-fluoro-4-methanesulfonyl-phenyl)-propan-2-one (AA3) following the procedure outlined in step (AA4), replacing thiourea with N-acetylthiourea. The titled compound crystallises from the reaction mixture.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C(OC)=O>[Cl-].[Na+].O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([N:12]([CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC=Cc1ccccc1
Reactant: CNc1ccccc1
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COC=O
Solvent: O
Product: CN(CC=Cc1ccccc1)c1ccccc1
Reaction time: 20 h
Yield: 91.4 %

Procedure:
Cinnamyl alcohol (100 mg, 0.75 mmol), N-methylaniline (53 mg, 0.50 mmol), dppf (14 mg, 0.025 mmol), K2CO3 (207 mg, 1.5 mmol) and [Pd(allyl)Cl]2 (4.5 mg, 0.0125 mmol) were sequentially added under argon to a reaction tube equipped with a stir bar and a septum. Degassed TPGS-M-PEG-750 solution (1.0 mL, 2 wt %), and HCO2Me (0.12 mL, 2.0 mmol) were added by syringe and vigorously stirred for 20 h. After the reaction, the contents of the flask were diluted with brine and extracted with EtOAc. The solution obtained was dried over anhydrous MgSO4, filtered, and concentrated by rotary evaporation. The residue was purified by flash chromatography eluting with 10% EtOAc/hexanes to afford the product as a pale yellow liquid (102 mg, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of piperazine-1-carboxylic acid tert-butyl ester (114 g) in DCM (500 mL) was cooled in an ice bath and treated with phenyl isocyanate (65 mL). After 1 hour (h), the bath was removed. After 15 h, the resulting mixture was filtered and the solid was washed with dichloromethane (DCM, 2×100 mL), giving the title compound as a white amorphous solid (95 g).
Reaction SMILES: O1CCOCC1.Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH2:17][C:18]([F:21])([F:20])[F:19])=[C:10]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])[N:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH3:28][C@H:23]1[CH2:24][O:25][CH2:26][CH2:27][N:22]1[C:10]1[N:9]=[C:8]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)[N:16]=[C:15]2[C:11]=1[N:12]=[CH:13][N:14]2[CH2:17][C:18]([F:21])([F:20])[F:19]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1ncn2CC(F)(F)F
Reactant: CC1(C)OB(c2cnc(N)nc2)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: O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(-c2cnc(N)nc2)nc2c1ncn2CC(F)(F)F
Yield: 99.3 %

Procedure:
Tetrakis triphenylphosphine (62 mg, 0.05 mmol) was added to a dioxane (5 ml)-water (1 ml) suspension of 2-chloro-6-[(3S)-3-methylmorpholin-4-yl]-9-(2,2,2-trifluoroethyl)-9H-purine (361 mg, 1.08 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (261 mg, 1.18 mmol), and sodium carbonate (342 mg, 3.23 mmol). The reaction mixture was heated to reflux for 2.5 hours and returned to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with 10% methanol-chloroform. The organic layer was dried over anhydrous magnesium sulfate and, after filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform:methanol=15:1) to give a solid. The resulting solid was washed with 50% ethyl acetate-hexane and dried to give the title compound (423 mg) as a powder.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][C:9]([Cl:12])=[N:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1.CC(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:3]2[C:2]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[N:8]=1
Reactant: Clc1ccc2c(Cl)ncnc2n1
Reactant: Nc1ccccc1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Clc1ccc2c(Nc3ccccc3)ncnc2n1
Reaction time: 48 h

Procedure:
A solution of Example 140D (0.5 g, 2.5 mmol), and aniline (0.23 mL, 2.5 mmol) in THF (25 mL) and 2-propanol (2.5 mL) was stirred at 0° C. for 1 h then at room temperature for 2 days. The THF was evaporated off and the residue was taken into ethyl acetate (75 ml), washed with water (50 ml) and brine (50 ml). The ethyl acetate was evaporated off and the residue was purified by flash column chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Recovered 0.15 g of product (23%). MS (ESI) m/z 390 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:20])(=[O:19])[NH2:18].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:16])[CH2:12][S:11][C:10](=[N:13][CH3:14])[N:9]2[CH3:15])=[CH:4][C:3]=1[S:17](=[O:19])(=[O:20])[NH2:18].[C:21]([O-:28])(=[O:27])/[CH:22]=[CH:23]\[C:24]([O-:26])=[O:25]
Reactant: O=C(O)/C=C\C(=O)O
Agent: CN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1C
Solvent: CCO
Product: O=C([O-])/C=C\C(=O)[O-]

Procedure:
1.5 g of 4-(4-chloro-3-sulfamoylphenyl)-3-methyl-2-methylimino-1,3-thiazolidine-4-ol were stirred in 10 ml of ethanol with 0.7 of maleic acid for 1 hour at room temperature, the salt desired was precipitated with 50 ml of diisopropyl ether and crystallized under fresh diisopropyl ether/ethyl acetate to yield colorless crystals which melted at 167° C. (decomposition).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)(=O)=O)=CC=1.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[C:40]1[CH2:41][CH2:42][NH:43][CH2:44][CH:45]=1>CS(C)=O.C(OCC)(=O)C>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[C:40]1[CH2:41][CH2:42][N:43]([CH2:12][CH:13]2[O:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]4[NH:25][C:24]([C:26]([F:29])([F:28])[F:27])=[N:23][C:20]4=3)[O:15][CH2:14]2)[CH2:44][CH:45]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6[nH]c(C(F)(F)F)nc6c5O4)CC3)c2c1
Temperature: 85 °C
Yield: 79.4 %

Procedure:
A mixture of 0.50 g (1.2 mmole) of [(8R)-2-trifluoromethyl-7,8-dihydro-3H-6,9-dioxa-1,3-diaza-cyclopenta[a]naphthalen-8-yl]methyl 4-methylbenzenesulfonate and 1.0 g (4.6 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 5.0 mL of DMSO was heated at 85° C. under nitrogen for 6 hours. The reaction was allowed to come to room temperature, diluted to 250 mL with ethyl acetate, washed with 250 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant and the product fractions concentrated in vacuum to give 0.45 g of the desired compound as the free base. Recrystallization from ethanol with the addition of 0.11 g of fumaric acid gave 0.25 g of the (S)-enantiomer of the title compound as a yellow solid hemifumarate, m.p. 236-238° C.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[O:14][C:15]2[C:24]3[CH:23]([CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[O:14][C:15]2[C:24]3[CH:23]([CH2:25][CH2:26][NH:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(CCCCOCc4ccccc4)oc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(CCCCO)oc3c21
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.6 %

Procedure:
To a solution of N-(2-{2-[4-(benzyloxy)butyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}ethyl)acetamide (79.5 mg, 0.196 mmol) in methanol (2 mL) was added a 10% palladium-carbon powder (160 mg), and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) to give the title compound (50.0 mg, yield 81%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:18])([CH3:17])[O:6][CH2:7][CH2:8][CH2:9][CH:10]([C:12]1[CH:16]=[CH:15][S:14][CH:13]=1)[OH:11])([CH3:4])[CH3:3].O[C:20]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:28][C:26]1[CH:27]=[CH:20][C:21]([C:22]#[N:23])=[C:24]([O:11][CH:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:9][CH2:8][CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:17])[CH3:18])[CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccsc1
Reactant: N#Cc1ccc(Cl)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCC(Oc1cc(Cl)ccc1C#N)c1ccsc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
The product from step (b) (1.164 g, 4.06 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml) and 2-hydroxy-4-chlorobenzonitrile (624 mg, 4.06 mmol) and triphenylphosphine (1.172 g, 4.47 mmol) added. The solution was cooled to 0° C. and diethyl azodicarboxylate (0.71 ml, 4.47 mmol) added dropwise. The reaction was allowed to warm to room temperature and stirred for a further 18 h. The reaction was concentrated in vacuo and the residue chromatographed on flash silica, eluting with hexane:ethyl acetate (4:1), to afford the title compound as a colourless oil (1.12 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][S:25]([CH3:24])(=[O:27])=[O:26])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.83 h
Yield: 6 %

Procedure:
To a stirred suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (216 mg) in pyridine (2 ml) was added a solution of methanesulfonyl chloride (78.4 mg) in dimethylformamide under ice-cooling, and the mixture was stirred for 50 minutes at the same temperature. The mixture was concentrated in vacuo, and ethyl acetate, methanol and water were added to the residue. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography and recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methanesulfonylhydrazino)quinoline (16 mg).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH:6]1([CH2:9][O:10][C:11]2[C:12]([O:23][CH3:24])=[CH:13][CH:14]=[C:15]3[C:20]=2[NH:19][C:18](=[O:21])[CH:17]=[C:16]3O)[CH2:8][CH2:7]1.C(O)(=O)C>C1(C)C=CC=CC=1>[NH2:5][C:16]1[C:15]2[C:20](=[C:11]([O:10][CH2:9][CH:6]3[CH2:8][CH2:7]3)[C:12]([O:23][CH3:24])=[CH:13][CH:14]=2)[NH:19][C:18](=[O:21])[CH:17]=1
Reactant: COc1ccc2c(O)cc(=O)[nH]c2c1OCC1CC1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(N)cc(=O)[nH]c2c1OCC1CC1
Yield: 72 %

Procedure:
Ammonium acetate (620 g, 8.0 mol) was added to a solution of 8-(cyclopropylmethoxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (105 g, 0.40 mol), acetic acid (400 mL), and toluene (200 mL). The reaction was refluxed with a Dean-Stark apparatus for 2 h, and then the mixture was concentrated to remove the toluene. The reaction was then refluxed overnight. Water/ice (200 mL) was added, and with external cooling, the pH was adjusted to 14 using 40% KOH. The resulting solids were collected by filtration and then purified by silica gel chromatography (100:1→30:1; dichloromethane/methanol) to give 75 g of 4-amino-8-(cyclopropylmethoxy)-7-methoxyquinolin-2(1H)-one as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 7.59 (d, 1H), 6.88 (d, 1H), 6.53 (s, 2H), 5.29 (s, 1H), 3.86 (s, 3H), 3.81 (d, 2H), 1.22 (m, 1H), 0.44 (m, 2H), 0.22 (m, 2H); MS (ESI): 261.1.