Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].CS(O[CH:17]1[CH2:22][CH2:21][CH:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:19][CH2:18]1)(=O)=O>CN(C=O)C>[Si:24]([O:23][CH:20]1[CH2:19][CH2:18][CH:17]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]2)[CH2:22][CH2:21]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2ccc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.7 %

Procedure:
To a solution of 3-trifluoromethyl-1H-pyrazole (1.0 g, 7.35 mmol) in DMF (10 mL) cooled in an ice bath was added NaH (0.3 g, 60% in mineral oil). The mixture was stirred for 10 minutes before the mesylate (1.13 g, 3.68 mmol) of step B in DMF (5 mL) was added. Stirring was continued at room temperature for 1 hour and then at 100° C. overnight. After being cooled to room temperature, the solution was poured into ice water and extracted with EtOAc three times. The combined extract was washed with brine, dried over MgSO4 and concentrated. Purification on silica gel eluting with 5:1 EtOAc/hexanes provided the title compound (0.56 g, 44%) as an oil. MS calculated (M+H)+ 349, found 349.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](O)=O)=[CH:3][N:2]=1.[C:10]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH2:23])=[C:19]([NH2:22])[CH:20]=2)[C:15]([CH3:25])([CH3:24])[CH2:14]1)(=[O:12])[CH3:11].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[C:10]([N:13]1[C:21]2=[CH:20][C:19]3[NH:22][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[N:23][C:18]=3[CH:17]=[C:16]2[C:15]([CH3:25])([CH3:24])[CH2:14]1)(=[O:12])[CH3:11]
Reactant: CC(=O)N1CC(C)(C)c2cc(N)c(N)cc21
Reactant: O=C(O)c1ccnnc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC(=O)N1CC(C)(C)c2cc3nc(-c4ccnnc4)[nH]c3cc21

Procedure:
To 75 g. polyphoshoric acid are added 3.1 g. pyridazine-4-carboxylic acid, 5.0 g. (23 mmole) 1-acetyl-5,6-diamino-3,3-dimethylindoline (Example 2b) and 22 g. phosphorus pentoxide and heated to 150°-160° C. for 7 hours. The reaction mixture is poured on to ice, rendered ammoniacal, extracted with dichloromethane and the extract evaporated to give 3.6 g. (51% of theory) of the title compound in the form of a dark solid; m.p. 225°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=[O:28].[CH3:36][S:37]([CH2:40][C:41](O)=[O:42])(=[O:39])=[O:38].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(=O)([O-])O.[Na+]>[CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:26])[C:4]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([C:41](=[O:42])[CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:34][CH2:35]1)=[O:28]
Reactant: CS(=O)(=O)CC(=O)O
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(=O)NC2CCN(C(=O)CS(C)(=O)=O)CC2)n(C)c2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 24.1 %

Procedure:
To a solution of the compound of Example 77 (200 mg, 0.423 mmol), (methylsulfonyl)acetic acid (76.0 mg, 0.550 mmol) and HOBt (85.8 mg, 0.635 mmol) in DMF (4 mL) was added WSCD (122 mg, 0.635 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted twice with ethyl acetate. The extract was combined, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by aminosilica gel chromatography (eluate; ethyl acetate). Recrystallization of the obtained solid from ethyl acetate gave the title compound (60.3 mg, 24%) as white crystals.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[CH:23]12[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[C:24]1=[O:33])[CH2:30]2.O>O1CCCC1>[OH:33][C:24]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH:23]2[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]1[CH2:26]3)[CH2:30]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)C3CC4CC(C3)CC2C4)cc1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred with 4.25 g of adamantanone for 1 hour at -70°, and heated to 25°. Then water is added, the mixture is extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, yielding 9 g of crude 4-(2-hydroxyadamant-2-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:21])[C:7](=[O:20])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([CH:17]([CH3:19])[CH3:18])[CH2:11]2)C>O.C(O)C>[CH:17]([CH:12]1[CH2:11][C:10]2[C:14](=[CH:15][CH:16]=[C:8]([C:7](=[O:20])[C:6]([OH:21])=[O:5])[CH:9]=2)[CH2:13]1)([CH3:19])[CH3:18]
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)CC(C(C)C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C1Cc2ccc(C(=O)C(=O)O)cc2C1

Procedure:
A solution of 10 g of sodium hydroxide in 20 cc of water is added to a solution of 24.5 g of crude 2-isopropyl-α-oxo-5-indanacetic acid ethyl ester in 300 cc of ethanol, and the mixture is boiled at reflux for 11/2 hours. The solution is concentrated, diluted with water, and the neutral by-products are extracted with ether. The aqueous phase is then acidified with hydrochloric acid, extracted with ether, the ether extract is washed with water, dried over sodium sulphate and concentrated by evaporation. 2-isopropyl-α-oxo-5-indanacetic acid is obtained as an oil and is used for the next reaction without purification. The (1,3-dihydroxy-2-hydroxymethyl-2-propyl)ammonium salt of 2-isopropyl-α-oxo-5-indanacetic acid has a M.P. of B 145°-147°.
Reaction SMILES: O=[C:2]([CH2:18][CH3:19])[CH2:3][NH:4][C:5]([C:7]1[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=2[CH:8]=1)=[O:6].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C1COCC1>[CH2:18]([C:2]1[O:6][C:5]([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:9]=3[CH:8]=2)=[N:4][CH:3]=1)[CH3:19]
Reactant: CCC(=O)CNC(=O)c1cc2c(OC)cccc2o1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Solvent: O
Product: CCc1cnc(-c2cc3c(OC)cccc3o2)o1
Yield: 83.8 %

Procedure:
To a solution of N-(2-oxobutyl)-4-methoxybenzo(b)furan-2-carboxamide (2.00 g) in THF (60 ml) was added Burgess reagent (7.30 g), and the mixture was stirred with refluxing. Water (200 ml) was added to the reaction mixture and the mixture was extracted with ether. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.56 g) as colorless crystals, melting point 88–87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5](C=O)=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([OH:26])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1Oc1ccccc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Cl)cc1Oc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A solution of 4-chloro-2-(2-fluoro-phenoxy)-benzaldehyde (0.8 g, 3.2 mmol) in chloroform (10 mL) is treated with m-CPBA (2.75 g, 16 mmol). The reaction is heated to reflux and stirred for about 2 hr. The reaction is cooled to room temperature and quenched with 10% aqueous NaHSO4. The aqueous is extracted with diethyl ether. The organic is washed with brine, dried over sodium sulfate, and the solvent is removed. The crude is diluted in methanol (20 mL) and treated with potassium carbonate (1.32 g, 9.6 mmol). The reaction stirred for 30 minutes at room temperature. The reaction is filtered and the solvent removed. The crude is purified by silica gel column chromatography using 4:1 hexanes:acetone to elute the pure product. The solvent is removed to afford about 0.64 g (84%) of product. 1H NMR (400 MHz, CDCl3). MS (ES−) m/z mass calcd for C12H8ClFO2 238, found 237 (M−1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N+:14]([O-])=[CH:13][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:25])C>>[OH:25][C:13]1[C:12]2[N:11]=[CH:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-n2cnc3c[n+]([O-])c4ccccc4c32)cc1
Product: COc1ccc(-n2cnc3c(O)nc4ccccc4c32)cc1

Procedure:
Using the method of Example 133, 1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinolin-5-oxide (from Exmaple 86) was reacted with acetic anhydride to provide 4-hydroxy-1-(4-methoxyphenyl)-1H-imidazo[4,5-c]quinoline m.p. >300° C. after recrystallization from N,N-dimethylformamide. Analysis: Calculated for C17H13N3O2 : %C, 70.1; %H, 4.5; %N, 14.4; Found: %C, 70.0; %H, 4.4; %N, 14.5.
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=O)[O:4][N:3]=1.[NH3:12]>CO>[Br:1][C:2]1[CH2:6][CH:5]([C:7]([NH2:12])=[O:9])[O:4][N:3]=1
Reactant: N
Reactant: CCOC(=O)C1CC(Br)=NO1
Solvent: CO
Product: NC(=O)C1CC(Br)=NO1

Procedure:
A mixture of ethyl 3-bromo-4,5-dihydroisoxazole-5-carboxylate (6.2 g, 28 mmol) and a solution of 2M ammonia in MeOH (56 mL) was stirred at room temperature for 1-2 h. Volatile materials were removed in vacuo to give the crude title compound as a white solid.
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Cl:15][CH:16]=[CH:17][CH2:18]Cl>CN(C)C=O>[CH2:1]([C:8]([CH2:18]/[CH:17]=[CH:16]/[Cl:15])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC(C#N)Cc1ccccc1
Reactant: ClC=CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(C/C=C/Cl)Cc1ccccc1
Yield: 36.4 %

Procedure:
Using 0.49 g of benzylmalononitrile, 15 ml of N,N-dimethylformamide, 0.14 g of sodium hydride (60% in oil), and 0.33 g of 1,3-dichloropropene, and according to the process described in the Production Example 1, there was obtained 0.25 g of 2-benzyl-2-((E)-3-chloro-2-propenyl)malononitrile (the present compound (60)) as high-polar compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccnc2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cccc2c(O)ccnc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
4-Hydroxyquinoline (1.45 g, 10 mmol) was dissolved in 3 ml of concentrated sulfuric acid and the solution was cooled -10° C. or less. The solution was gradually added with mixed acid (0.8 ml of concentrated nitric acid with 1.2 ml of concentrated sulfuric acid) such that the reaction solution was not elevated in temperature up to 0° C. or more, and stirred at 0° C. for 3 hours. The reaction mixture was poured into crashed ice and neutralized with 2N aqueous solution of sodium hydroxide. The resulting precipitates were filtered off and washed with water. The filtrate was combined with the washing solution and extracted with methylene chloride. After drying over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was developed by silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=20 : 1). Firstly eluted yellow fractions were collected and the solvent was removed to obtain 380 mg (20%) of 4-hydroxy-8-nitroquinoline.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20])=[N+]=[N-].[H][H]>O.CO.[Pd]>[NH2:1][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20]
Reactant: [H][H]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O

Procedure:
5'-Azido-5-ethyl-2',5'-dideoxyuridine (300 mg) is dissolved in a mixture of water-methanol (1:1, 25 ml) and then hydrogen gas is introduced with 10% Pd/C at room temperature under 1 atmosphere for 2 hr, after which the mixture is filtered and the filtrate is evaporated to a foam (160 mg, 50%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[CH3:15][NH2:16].CO>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:16][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CN
Reactant: COC(=O)CCCc1ccc(N)cc1
Solvent: CO
Product: CNC(=O)CCCc1ccc(N)cc1
Yield: 95 %

Procedure:
A solution of compound 27 (450 mg, 2.33 mmol) in CH3NH2/CH3OH (29, 50 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated to dryness to give compound 30 (450 mg, 95%) as a white solid. The crude product was used directly for the next step without purification. 1H NMR (400 MHz, CDCl3) δ6.95 (d, 2H, J=8.3 Hz), 6.61 (d, 2H, J=8.3 Hz), 5.30 (br s, 1H), 3.50 (br s, 2H), 2.78 (d, 3H, J=4.8 Hz), 2.54 (t, 2H, J=7.4 Hz), 2.14 (t, 2H, J=7.4 Hz), 1.85-1.95 (m, 2H).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:48][O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[CH2:56][CH2:57][NH2:58]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:58][CH2:57][CH2:56][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=4[O:49][CH3:48])=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: COc1ccccc1CCN
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCCc2ccccc2OC)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-(2-methoxy-phenyl)-ethylamine (Fluka) to give the title compound. HR-MS (ES, m/z) calculated for C44H53Cl2N6O4 [(M+H)+] 799.35, observed 799.3496.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][Br:9])[CH:5]=[CH:4][C:3]=1[CH2:10][OH:11]>CCO.CCOC(C)=O.O=[Mn]=O>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:10]=[O:11])=[C:2]([Br:1])[CH:7]=1
Reactant: OCc1ccc(CBr)cc1Br
Agent: O=[Mn]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CBr)cc1Br
Yield: 80.6 %

Procedure:
The compound of Step 2 (8 g, 29 mmol, 1 eq) was dissolved in 10% EtOH/EtOAc (300 ml) and 5 eq of MnO2 (12.4 g, 142 mmol) was added every hour for 6 hours. The mixture was filtered through Celite and solvent was removed. 6.5 g (80%) of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1>>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:7][C:6]2[CH:19]=[CH:20][C:21]3[NH:22][C:31]([C:30]4[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=4)=[N:1][C:4]=3[CH:5]=2)=[O:18])=[CH:10][CH:11]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc(N(C)C)cc4)nc3c2)cc1

Procedure:
Compound 206 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (300 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.39 (s, 1H), 8.11 (d, J=8 Hz, 2H), 7.90 (d, J=9 Hz, 2H), 7.81 (d, J=9 Hz, 2H), 7.68 (d, J=9 Hz, 2H), 6.95 (d, J=9 Hz, 2H), 6.78 (d, J=9 Hz, 2H), 3.07 (s, 6H), 2.99 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Yield: 87 %

Procedure:
To a solution of 5a in methanol were added catalytic amounts of Pd on carbon. Reaction mixture was stirred at 20 psi of hydrogen overnight. Solid was filtered off and methanol was removed in vacuo to afford 8-amino-2-phenyl-2,5-dihydro-pyrazolo-(4,3-c) quinolin-3-one in 87% yield. 1H-NMR (DMSO-d6) δ (ppm): 6.92 (1H, dd, J=8.79, 2.47 Hz), 7.13 (1H, m), 7.28 (1H, d, J=2.47 Hz), 7.43 (3H, m), 8.20 (2H, dd, J=7.69, 1.10 Hz), 8.44 (1H, d, J=6.59 Hz). m/z 277.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[CH3:30][N:31]([CH2:35][CH2:36]O)[CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:36][CH2:35][N:31]([CH2:32][CH2:33][OH:34])[CH3:30])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CN(CCO)CCO
Product: CN(CCO)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and N-methyldiethanolamine following General Procedure K.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[F:5][C:6]1[CH:25]=[CH:24][C:9]([C:10]([NH:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15])=[O:11])=[CH:8][CH:7]=1.[Na]>C(O)C>[OH:20][C:19]1[C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:24]=[CH:25][C:6]([F:5])=[CH:7][CH:8]=2)=[C:14]([OH:15])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Reactant: NC(N)=S
Agent: [Na]
Solvent: CCO
Product: O=C(Nc1c(O)nc(S)nc1O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
Thiourea (0.72 g, 9.4 mmol) and diethyl 2-(4-fluorobenzamido)malonate (example 1, 2.0 g, 6.7 mmol) were added to a solution of sodium (0.16 g, 6.7 mmol) in ethanol (50 ml). The reaction mixture was refluxed for 3 hours and then cooled down to room temperature. The precipitate was filtered off and washed with ethanol. The product was dissolved in a minimal volume of water and acidified to pH 4-5 with 5M HCl. The precipitate was collected, washed with water and dried, furnishing the title compound as a white solid (0.78 g, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](Cl)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[OH:12][CH2:13][CH:14]([CH2:16][OH:17])[OH:15].[OH-].[Na+]>O>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][O:12][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH2:1])[CH:3]=1
Reactant: OCC(O)CO
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(OCC(O)CO)ccc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
0.1 mol (17.3 g) of 3-amino-4-nitro-chlorobenzene, which is a known compound [Bios Final Report, 1,147 (1948)], is introduced gradually, at about 120° C., whilst stirring, into 2.4 mols (225 g) of glycerol in which 8.6 g of sodium hydroxide have been dissolved beforehand at about 120° C. When the addition has ended, heating is continued for 21/2 hours and the reaction medium is then poured into 250 g of iced water. The desired product is extracted with ethyl acetate and the ethyl acetate is driven off in vacuo to give 13.6 g of crystalline product. After two recrystallisations from acetonitrile and drying in vacuo, 3-amino-4-nitrophenyl β,γ-dihydroxypropyl ether, which melts at 139° C., is collected.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH2:6][CH:5]([C:12]2SC=C[CH:16]=2)[N:4]=1.[H][H]>[Pd].C(O)C>[ClH:1].[NH2:2][C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH2:6][CH:5]([CH2:12][CH3:16])[N:4]=1
Reactant: NC1=NC(c2cccs2)Cc2ccsc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCC1Cc2ccsc2C(N)=N1
Yield: 65.2 %

Procedure:
Palladium on charcoal (57 mg) was added as a slurry in ethanol to 7-amino-5-ethynyl-4,5-dihydrothieno[2,3-c]pyridine hydrochloride (Example 56) (113 mg, 0.531 mmol) in ethanol (6 ml) and the mixture stirred for 16 h under 3 atm. of hydrogen. The mixture was then filtered through celite, evaporated and triturated with dichloromethane to afford a white powder (75 mg), m.p. 221-223° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=O)[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([NH:47][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:16])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)NCCc1ccccc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a stirred solution of Boc-Asp(OBzl), 5.0 g (15.5 mmol) and N-methyl morpholine (15.5 mmol) in 50 mL of dry THF under an Ar atmosphere was added isobutylchloroformate (15.5 mmol) at -15° C. After a few minutes, phenethylamine 2.0 mL (15.5 mmol) in 15 mL of dry THF was added. The mixture was maintained at -15° C. for 15 min. and allowed to warm to room temperature. After stirring for an additional 2 hours, the reaction mixture was filtered and the filtrate was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (100 mL) and washed successively with 1M HCl (2×50 mL), water (50 mL), 10% sodium carbonate (2×50 mL), and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to yield 5.59 gm (85%) of an amorphous white solid.