Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]([CH2:12][OH:13])=[N:10][C:9]2[NH:8][C:7](=[O:14])[CH2:6][S:5][C:4]=2[CH:3]=1.C1COCC1>[O-2].[O-2].[Mn+4].ClCCCl>[F:1][C:2]1[C:11]([CH:12]=[O:13])=[N:10][C:9]2[NH:8][C:7](=[O:14])[CH2:6][S:5][C:4]=2[CH:3]=1
Reactant: O=C1CSc2cc(F)c(CO)nc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=Cc1nc2c(cc1F)SCC(=O)N2
Temperature: 60 °C

Procedure:
A mixture of the alcohol (e) (971 mg), manganese dioxide (3.72 g), THF (70 ml) and 1,2-dichloroethane (70 ml) was heated at 60° C. under argon for 20 hours. Filtration through kieselguhr and evaporation of solvent gave a solid which was triturated with EtOAc/hexane 1:3 and collected by filtration (608 mg).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:21][C:22]1[N:23]=[C:24]([CH:27]=[CH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([C:37]([F:40])([F:39])[F:38])=[O:36])=[CH:31][CH:30]=2)[O:25][CH:26]=1.O>CN(C=O)C>[F:40][C:37]([F:38])([F:39])[S:35]([C:32]1[CH:33]=[CH:34][C:29](/[CH:28]=[CH:27]/[C:24]2[O:25][CH:26]=[C:22]([CH2:21][O:19][C:16]3[CH:15]=[CH:14][C:13]([CH2:12][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[O:11])=[CH:18][CH:17]=3)[N:23]=2)=[CH:30][CH:31]=1)=[O:36]
Reactant: O=S(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(S(=O)C(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h
Yield: 47.2 %

Procedure:
14 mg (0.55 mmol) 95% sodium hydride were given to a solution of 126 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfinylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 6 ml water the resulting precipitate was collected and combined with additional material obtained by extraction of the aqueous phase at pH=3 with ethyl acetate, drying (sodium sulfate) and evaporation. Purification by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1) gave 130 mg (77%) powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([C:14]#[C:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([NH:1][C:16](=[O:17])[C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Nc1ccccc1
Product: O=C(C#Cc1ccccc1)Nc1ccccc1
Yield: 79.8 %

Procedure:
According to preparation 15, aniline (0.700 g, 7.5 mmol) was coupled to phenylpropiolic acid (1.0 g, 6.8 mmol) to provide 1.2 g (73%) of product. NMR.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[N:27]=[CH:26]1>>[NH:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]3[C:2]4[N:3]=[C:4]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[N:5]=[C:6]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=5)[C:7]=4[CH2:8][CH2:9]3)=[CH:33][C:28]=2[N:27]=[CH:26]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc3[nH]cnc3c2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 1H-benzimidazol-5-ylamine, the desired compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:13]([C:20](OCC)=[O:21])#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[O:10]1[CH2:9][CH2:8][N:7]([C:4]2[S:3][C:2]3=[N:1][C:20](=[O:21])[CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:6]3[N:5]=2)[CH2:12][CH2:11]1
Reactant: Nc1nnc(N2CCOCC2)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCOCC3)nn12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3.5 g of the 2-amino-5-morpholino-1,3,4-thiadiazole obtained in Example 1 were mixed with 40 ml of absolute ethanol and then 3.2 g of diethyl acetylendicarboxylate was added. The reaction mixture was heated on a water bath to about 60° C. until a clear solution was formed. This was stored overnight at room temperature and then evaporated in vacuo to dryness. The residue was triturated with a small amount of cold ethanol, filtered off, washed with ether and finally dried. Thus 3.8 g, corresponding to 65.2% of the theoretical yield, of ethyl 2-morpholino-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylate, melting at 151° to 153° C., was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23].[CH:25](O)=[O:26]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:25]=[O:26])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:20])([CH3:22])[CH3:21])=[CH:15][C:14]=1[F:23]
Reactant: O=CO
Reactant: COC(=O)c1ccc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 89 %

Procedure:
A solution of 6-aminomethyl-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (13.2 g, 38.2 mmol) in formic acid (200 mL) and acetic anhydride (40 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue azeotroped with toluene. The resultant residue was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogen carbonate, followed by brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a yellow solid (12.7 g, 89%). LCMS (method B): RT=4.17 min, M+H+=376.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:29])([F:28])[F:27])[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br:32]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>ClCCCl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:13]2([C:26]([F:27])([F:28])[F:29])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH:24]([Br:32])[CH3:25])=[CH:22][CH:23]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClCCCl
Product: CC(Br)c1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Temperature: 25 °C

Procedure:
To a solution of 3.00 g of 5-[3,5-bis(trifluoromethyl)phenyl]-3-(4-ethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 15 mL of 1,2-dichloroethane, 1.29 g of N-bromosuccinimide and 0.10 g of α,α′-azobisisobutyronitrile were added and the resultant mixture was stirred at 75° C. for 3 hours. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature and then 10 mL of water was added to the reaction mixture. The resultant mixture was extracted with chloroform (20 mL×1). The organic phase was washed with water (10 mL×1) and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.01 g of the objective substance as a white crystal.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([O:23]C)=O)=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:14]1[CH2:13][CH2:12][CH:11]([CH2:10][CH:9]2[NH:8][C:21](=[O:23])[CH2:20][NH:19][C:17]2=[O:18])[CH2:16][CH2:15]1
Reactant: COC(=O)CNC(=O)[C@H](CC1CCOCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNC(=O)C(CC2CCOCC2)N1
Reaction time: 0.17 h
Yield: 77.9 %

Procedure:
A 250 mL round-bottomed flask was charged with methyl N-(tert-butoxycarbonyl)-3-(tetrahydro-2H-pyran-4-yl)-alanylglycinate (3.00 g, 8.71 mmol), 10 mL of CH2Cl2, and 5 mL of TFA. After 10 min, the mixture was concentrated then re-dissolved in MeOH (50 mL) and triethylamine (10 mL) and then heated at reflux for 18 h. After that time, the white precipitate formed was collected by filtration to give 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Product: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-chloro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J14) (311 mg, 1.0 mmol) and 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid tert-butyl ester (Example K16) (286 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (160 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:22]2[CH:21]=[C:6]([O:7][C:8]3[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]4[C:9]=3[CH2:10][CH2:11][CH2:12]4)[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:29])=[CH:26][CH:25]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C(=O)c1ccc(F)cc1

Procedure:
4-(4-methoxyphenoxy)-5-methyl-7-nitroindane (197 mg) and 4-fluorobenzoyl chloride (194 μL) were dissolved in dichloromethane (3.9 mL). Titanium tetrachloride (360 μL) was added dropwise to the solution under ice-cooling with stirring. The mixture was stirred under an argon atmosphere at room temperature for 15 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=9/1) to give (4-fluorophenyl)-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)phenyl]methanone (155 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O>>[Br:1][C:2]1[CH:3]=[C:4]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10]
Reactant: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(I)cc1
Reactant: OB(O)c1cccs1
Product: O=S(=O)(Nc1ccc(OC(F)(F)F)c(Br)c1)c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 126-196. MS (ES−) m/e 476/478 [M−H]−.
Reaction SMILES: [O-]CC.[Na+].C([O:7][C:8](=O)[CH:9]([CH:16]=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])C.[NH2:19][C:20]([NH2:22])=[S:21].C(O)(=O)C>C(O)C>[O:7]=[C:8]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][NH:22][C:20](=[S:21])[NH:19]1
Reactant: CCOC(=O)CC(C=O)C(=O)OCC
Reactant: NC(N)=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)Cc1c[nH]c(=S)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Sodium ethoxide (6.105 g, 89.71 mmol) was added to absolute ethanol (150 mL) under an atmosphere of nitrogen followed by diethyl-2-formylsuccinate (1105) (crude, 16.5 g) in absolute ethanol (30 mL) and thiourea (6.829 g, 89.71 mmol). The reaction mixture was heated at reflux for 1 hour then cooled to room temperature at which stirring was continued for 16 hours. The volatiles were evaporated under reduced pressure to give a brown oily solid. Cold aqueous acetic acid solution (15%; 120 mL) was added and the resulting mixture was sonicated and then stirred at 0° C. until all the residue was in suspension. The resulting precipitate was collected by filtration. The filter cake was washed with water (100 mL) and dried to give the title compound (I106) (6.31 g, 19% yield over 2 steps) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 7.44 (s, 1H), 4.05 (q, J=7.1 Hz, 2H), 3.28 (s, 2H), 1.17 (t, J=7.1 Hz, 3H). LCMS Method C: rt 2.92 min; m/z 213.0 [M−H]−.
Reaction SMILES: [OH:1][C@@H:2]([CH3:35])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[N:14](CC3C=CC=CC=3)[C:13]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:12][C:11]=2[N:10]([CH3:34])[C:8]1=[O:9].[H][H]>C(O)C.[Pd]>[OH:1][C@@H:2]([CH3:35])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:16](=[O:17])[C:15]2[NH:14][C:13]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])=[N:12][C:11]=2[N:10]([CH3:34])[C:8]1=[O:9]
Reactant: C[C@H](O)CCCCn1c(=O)c2c(nc(CNC(=O)OC(C)(C)C)n2Cc2ccccc2)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](O)CCCCn1c(=O)c2[nH]c(CNC(=O)OC(C)(C)C)nc2n(C)c1=O
Yield: 81.6 %

Procedure:
To a solution of (S)-1-(5-hydroxyhexyl)-7-benzyl-8-(N-BOC-aminomethyl)-3-methylxanthine (0.6 g, 1.24 mmol) in ethanol (60 ml) was added 10% palladium on carbon catalyst (0.5 g). The mixture was treated with hydrogen gas (50 psi) on a Parr shaker for 18 hours. Removal of the catalyst by filtration and evaporation of the solvent under reduced pressure provides (S)-1-(5-hydroxyhexyl)-8-(N-BOC-aminomethyl)-3-methylxanthine (0.4 g, 82% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 39.4 %

Procedure:
2-Bromophenol (50.0 g, 0.289 mol) was dissolved in acetone (400 ml) and after adding thereto in sequence anhydrous potassium carbonate (79.89 g, 0.578 mmol) and benzyl bromide (59.32 g, 0.347 mol), the solution was refluxed under heating for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane:AcOEt=95:5) to obtain the titled compound (30.0 g, 0.114 mol, 40%).
Reaction SMILES: [Na].Cl.[C:3]1([CH3:12])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([NH2:11])=[NH:10])[CH:4]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15](OCC)=[O:16]>C(O)C>[C:3]1([CH3:12])[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[NH:10][C:13](=[O:20])[CH2:14][C:15](=[O:16])[N:11]=2)[CH:4]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cccc(C(=N)N)c1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(C2=NC(=O)CC(=O)N2)c1

Procedure:
To a stirred solution of 35.8 g. of sodium metal in one liter of absolute ethanol, there is added 88.5 g. of m-toluamidine hydrochloride followed by the dropwise addition of 91.5 g. of diethyl malonate over a fifteen minutes period. The reaction mixture is heated under reflux for four hours. The solution is filtered and the filter cake dissolved in water. The ethanol filtrate is evaporated to dryness and the solid residue added to the water solution. Upon acidification of the aqueous solution to pH2 with concentrated hydrochloric acid, a solid separates which is removed by filtration. After washing this material several times with water, the product is recrystallized from aqueous N,N-dimethylformamide to afford 2-(3-tolyl)-4,6-(1H,5H)-pyrimidinedione, m.p. 247.5°c.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:14]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCO)CC1

Procedure:
A suspension of 3.4 g (12.72 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 125 ml ethanol and 810 mg of PtO2.H2O was hydrogenated (1 atm) for 7 h. The reaction was filtered (Celite) and evaporated to give 3.5 g (quantitative) of trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 271 (MH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[Cl:13]N1C(=O)CCC1=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:13])[CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1CCc2cc(Br)ccc2N1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(Cl)c2N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-bromo-3,4-dihydroquinolin-2(1H)-one (74-3; 20 g, 0.088 mol) in N,N-dimethylformamide (200 mL) was added N-chlorosuccinimide portion wise (17.7 g, 0.132 mol) at 80° C. Reaction mass was allowed to stir at 80° C. for 2 h. The reaction mixture was cooled and diluted with ice cold water. The precipitated solid filtered and dried to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (bs, 1H), 7.52-7.51 (d, J=1.6 Hz, 1H), 7.41 (s, 1H), 2.93-2.90 (t, J=8 Hz, 2H). MS (M+1); 261.2.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Cl>CC(O)C.CCOCC.[Fe]>[NH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:32])([F:31])[F:1])[C:4]([F:5])([F:6])[F:7])=[CH:14][CH:13]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: [Fe]
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: Nc1ccc(N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Yield: 50.8 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-((4-(4-nitrophenyl)piperazin-1-yl)methyl)phenyl)propan-2-ol (17.26 mmol, 8 g) and iron (143 mmol, 8 g) in 2-propanol was added 2M hydrochloric acid. The reaction was refluxed for 3 hours. The reaction was filtered through celite washing with 2-propanol and concentrated under reduced pressure. Water and ethyl acetate was added. Solid potassium carbonate was added until the aqueous layer was basic. The organic phase was separated and the water layer was extracted with dichloromethane. The combined organic phases were combined, dried (sodium sulfate) and concentrated under reduced pressure. The crude material was chromatographed on silica eluting with ethyl acetate. The brown solid obtained was stirred in ether and filtered to give the title compound (3.8 g). MS (ESI) m/z 434.1 [M+H]+
Reaction SMILES: Cl.[NH2:2][OH:3].CC([O-])(C)C.[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[CH:24]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1>CS(C)=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:33])([F:35])[F:34])[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([C:27]([NH:2][OH:3])=[NH:28])=[C:25]([CH3:31])[CH:24]=3)[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: NO
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=N)NO
Temperature: 80 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
A solution hydroxylamine hydrochloride (8.70 g) in DMSO was cooled to 15° C., before KOtBu was added in small portions. This mixture was added to a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzonitrile (5.00 g) in DMSO (20 mL) at room temperature and stirred at 80° C. for 5 h. After completion of the reaction, the mixture was poured onto ice-water and the resulting solid was collected by filtration, washed with water and dried. Chromatography on silica gel yielded the title compound (3.3 g, 61%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[NH:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[C:18]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:17]=1)=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([CH:29]=[CH:28][C:18]2[N:17]=[C:16]([NH:15][C@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]3[NH2:8])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2nc(C=Cc3ccc(Cl)cc3)nc(N[C@H]3CCCC[C@H]3N)c2c1
Yield: 90.5 %

Procedure:
A solution of 520 mg of cis-N-tert-butoxycarbonyl-2-[2-(4-chlorostyryl)-6-methoxyquinazolin-4-yl]aminocyclohexylamine in 10 mL of methanol was combined with 5 mL of a 4 N solution of hydrogen chloride in ethyl acetate, and reacted at 50° C. for 24 hours. After the solvent was distilled off, the residue was basified by addition of a 10% aqueous solution of sodium hydroxide, and extracted with chloroform. After concentrating, the residue was purified by column chromatography on silica gel (chloroform:methanol=10:1) to obtain 378 mg of the desirable compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([OH:22])=[O:21].C([O-])(O)=O.[Na+:27]>C(O)C.O>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:5]=[C:4]([CH3:19])[C:3]=1[C:20]([O-:22])=[O:21].[Na+:27]
Reactant: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc2cccc(OC3CCCCC3)c2c(N)c1C(=O)[O-]
Temperature: 60 °C
Yield: 99.7 %

Procedure:
To a solution of 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylic acid (Example 36, 1.0 g, 3.33 mmol) in ethanol (20 mL) was added a solution of NaHCO3 (294 mg, 3.50 mmol) in water (15 mL). The mixture was stirred and warmed up to 60° C. until the solution become clear then evaporated to dryness to provide sodium 4-amino-5-(cyclohexyloxy)-2-methylquinoline-3-carboxylate (1.07 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.45 (m, 3H), 1.50-1.70 (m, 5H), 1.53-1.72 (m, 5H), 1.98-2.00 (m, 2H), 2.64 (s, 3H), 4.59-4.63 (m, 1H), 6.87-6.89 (d, J=7.6 Hz, 1H), 7.20-7.22 (d, J=8.0 Hz, 1H), 7.42 (t, J=8.0 Hz, 1H). MS 301 (MH++H-Na).