Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1)([O-])=O>[Pt]=O.C(O)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14](=[O:20])[NH:15]3)=[CH:6][CH:5]=1
Reactant: O=c1ccc2c(-c3ccc([N+](=O)[O-])cc3)nccc2[nH]1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: Nc1ccc(-c2nccc3[nH]c(=O)ccc23)cc1
Reaction time: 1 h
Yield: 54.8 %

Procedure:
A mixture containing 10.68 g of 5-(4-nitrophenyl)-1,6-naphthyridin-2(1H)-one, 1 g of platinum oxide and 300 ml of acetic acid was catalytically hydrogenated in a Paar hydrogenator at room temperature over a period of about 1 hour. The catalyst was filtered off and the filtrate was concentrated on a rotary evaporator. The residue was slurried in boiling methanol, the mixture filtered, and the collected solid washed with methanol and dried in a vacuum oven at about 90° C. The solid was then recrystallized using 100 ml of boiling dimethylformamide and decolorizing charcoal, filtering the hot mixture, and concentrating the filtrate on a rotary evaporator. The remaining solid was slurried with methanol, the mixture filtered and the collected solid dried in a vacuum oven at 90° C. to yield 5.2 g of 5-(4-aminophenyl)-1,6-naphthyridin-2(1H)-one, m.p. 309°-312° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[NH:26][CH:25]=[C:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31](=[O:32])[C:30]1[CH:29]=[CH:28][C:27]([C:24]2[CH:23]=[CH:22][C:21](=[O:20])[NH:26][CH:25]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2ccc(=O)[nH]c2)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(-c2ccc(=O)[nH]c2)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(6-oxo-1,6-dihydro-pyridin-3-yl)-benzoic acid. MS: 457.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:14][CH2:15][CH2:16][NH:17][CH2:18][C:19]([OH:21])=O)[C:12]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[CH:11][S:10]2)=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36].C(N(C(C)C)CC)(C)C.N=C=N>ClCCl.CN(C)C=O>[CH2:35]([NH:37][C:19](=[O:21])[CH2:18][NH:17][CH2:16][CH2:15][CH2:14][N:13]1[C:12]([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:26][CH:27]=2)=[CH:11][S:10][C:9]1=[N:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH3:36]
Reactant: CCN
Reactant: O=C(O)CNCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Agent: Cl
Agent: N=C=N
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CNCCCn1c(-c2ccc(N3CCOCC3)cc2)csc1=Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was synthesized by combinatorial chemistry technique. That is, to a solution of the compound obtained in Example 329 (2) in dichloromethane (43.8 μmol/ml) (1 ml) were added a solution of ethylamine hydrochloride in N,N-dimethylformamide (35.0 μmol/ml) (1 ml), a solution of diisopropylethylamine (35.0 μmol/ml) (1 ml) and a suspension of carbodiimide resin in dichloromethane (79.2 mg/ml, manufactured by Argonaut) (1 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (2 ml), and then washed twice with water (2 ml). The organic layer was passed through a filter containing magnesium sulfate, and the filter was washed twice with dichloromethane (1 ml), and the filtrate was concentrated. To the residue was added a 90% trifluoroacetic acid (2 ml), and the mixture was stirred at room temperature for 2 hours, and concentrated. The residue was dissolved in dichloromethane (2 ml), and excess amount of ion-exchange resin (Dowex 1-X8, OH-type) was added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was washed twice with dichloromethane (1 ml), and the filtrate was concentrated to give the title compound (6 mg).
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.O>[N:21]([CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20])=[N+:22]=[N-:23]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(N=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.1 %

Procedure:
Ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.55 g) was dissolved in N,N-dimethylformamide (30 ml); a solution of sodium azide (0.88 g) in water (5 ml) was added at 0° C. After the reaction mixture was stirred at room temperature for 50 minutes, it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9, v/v) to yield ethyl 5-azido-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.70 g, 74.2%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 118-119° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:12][C:10]1([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[CH:7]=[C:2]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=[C:4]2[NH:11]1
Reactant: C1COCCN1
Reactant: CC1(C)Cn2c(nc(Cl)cc2=O)N1
Product: CC1(C)Cn2c(nc(N3CCOCC3)cc2=O)N1
Temperature: 120 °C

Procedure:
A mixture of 1 g of 7-chloro-2,2-dimethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 10 ml of morpholine is heated at 120° C. for 1 hour. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by silica chromatography (eluent: CH2Cl2/MeOH 97/03) so as to give 650 mg of 2,2-dimethyl-7-morpholin-4-yl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]2[CH2:7][N:8]([C@H:10]3[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[F:24])[C@@H:12]([NH:25]C(=O)OC(C)(C)C)[CH2:11]3)[CH2:9][C:3]=12.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].C(Cl)Cl>>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[NH2:25][C@@H:12]1[C@@H:13]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[N:14]([CH3:16])[CH2:15][C@H:10]([N:8]2[CH2:9][C:3]3[C:4](=[N:5][NH:6][C:2]=3[NH2:1])[CH2:7]2)[CH2:11]1
Reactant: CN1C[C@H](N2Cc3n[nH]c(N)c3C2)C[C@H](NC(=O)OC(C)(C)C)[C@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@H](N2Cc3n[nH]c(N)c3C2)C[C@H](N)[C@H]1c1cc(F)ccc1F

Procedure:
The product from step B was treated with 1:1 TFA/CH2Cl2 for 1 h. The solvent was removed by evaporation under diminished pressure and residue dried under vacuum to give the title compound. LC-MS: 349.0 (M+1).
Reaction SMILES: [OH2:1].O.[Cl-].[Ca+2].[Cl-].O.[CH2:7]([C:9]1([CH3:20])N=[C:13]([CH2:15][CH3:16])[CH2:12][C:11]([CH2:18][CH3:19])([CH3:17])[NH:10]1)[CH3:8].[OH-].[Na+]>C(C(C)=O)C>[CH2:7]([C:9]1([CH3:20])[CH:15]([CH3:16])[C:13](=[O:1])[CH2:12][C:11]([CH2:18][CH3:19])([CH3:17])[NH:10]1)[CH3:8]
Reactant: O
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Temperature: 60 °C
Reaction time: 15 h
Yield: 164.2 %

Procedure:
First 14.7 g of powdered calcium chloride dihydrate and then 3 ml of water were added to an ice-cooled mixture of 39.2 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine and 18.0g of methyl ethyl ketone. The resulting mixture was heated at 60° C with stirring for 15 hours made alkaline with 35% aqueous sodium hydroxide solution, and extracted with diethyl ether. The extract was dried over potassium carbonate and the ether was evaporated off. The residue was distilled under reduced pressure, to give 32.4 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])\[CH2:16][CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])\[CH2:16][CH3:17])=[CH:10][CH:11]=1
Reactant: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(OCOC)cc1)c1ccccc1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 4a (75 mg, 0.153 mmol) in MeOH (2 ml) was added 4N HCl in 1,4-dioxane (0.4 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residual was crystallized with AcOEt to give 5a (74%). 5a: colorless powder; 1H-NMR (CD3OD) δ 0.97 (3H, t, J=7.5 Hz), 2.09 (3H, s), 2.37 (6H, s), 2.58 (2H, q, J=7.5 Hz), 2.80 (2H, t, J=5.5 Hz), 4.11 (2H, t, J=5.5 Hz), 6.47 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=9.1 Hz), 6.94 (2H, d, J=9.1 Hz), 7.05-7.15 (4H, m), 7.53 (2H, d, J=9.1 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2497.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[NH:23]1[C:31]2[C:26](=[CH:27][C:28](B(O)O)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1>O1CCOCC1.O.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>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([C:2]3[CH:3]=[C:4]([C:9]4[O:10][C:11]([CH:14]([CH3:16])[CH3:15])=[N:12][N:13]=4)[C:5]([NH2:8])=[N:6][CH:7]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CC(C)c1nnc(-c2cc(Br)cnc2N)o1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nnc(-c2cc(-c3ccc4[nH]ccc4c3)cnc2N)o1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-3-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (250 mg, 0.883 mmol) in dioxane (15 mL) and water (7 mL) were added K2CO3 (365 mg, 2.649 mmol), indole-5-boronic acid (156 mg, 0.971 mmol) in a sealed tube. The reaction mixture was degassed by N2 for 20 min, then Pd(PPh3)4 (102 mg, 0.088 mmol) was added and stirred for 18 h at 100° C. Water (20 mL) was added and extracted with ethyl acetate (3×20 mL) and the organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. Crude product was purified by column chromatography using 100-200 mesh silica gel compound eluted with 40% ethyl acetate in petroleum ether to afford the title compound as a yellow solid.
Reaction SMILES: OS(O)(=O)=O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[I:21]>O>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([N+:6]([O-:9])=[O:7])[C:12]=1[I:21]
Reactant: Cc1cc(C(F)(F)F)ccc1I
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(F)(F)F)cc([N+](=O)[O-])c1I
Temperature: 0 °C

Procedure:
A 1:1 mixture of H2SO4/HNO3 (20 ml) was added to 2-methyl-4-trifluoromethylphenyl iodide at 0° C. The mixture was stirred at 0° C. and then warmed to room temperature overnight. LC/MS analysis indicated no remaining starting material. The mixture was diluted with water and extracted with EtOAc (3×50 ml). The combined EtOAc layers were washed with sodium bicarbonate and brine and dried over sodium sulfate. The title compound was obtained after removal of solvent. 1H NMR (CDCl3, 500 MHz): δ 7.71 (s, 1H), 7.69 (s, 1H), 2.68 (s, 3H).
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]([CH2:27][S:28]([C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:30])=[O:29])[C:20](=[O:26])[C@@H:21](Br)[C@H:22]([OH:24])[CH3:23])=[CH:16][CH:15]=1.C(Cl)Cl>O1CCCC1>[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]([CH2:27][S:28]([C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:30])=[O:29])[C:20](=[O:26])[C@@H:21]2[O:24][C@@H:22]2[CH3:23])=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(CS(=O)(=O)C(C)(C)C)C(=O)[C@@H](Br)[C@@H](C)O)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CN(CS(=O)(=O)C(C)(C)C)C(=O)[C@@H]2O[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
At -14° with the exclusion of moisture, 340 ml of 1,5-diazabicyclo[5.4.0]undec-5-ene in 1 ml of tetrahydrofuran are added to a solution of 486 mg (1.1 mmol) of (2S,3R)-N-p-methoxybenzyl-N-tert.-butylsulphonylmethyl-2-bromo-3-hydroxybutyramide in 8 ml of tetrahydrofuran. The solution is stirred at room temperature for 75 minutes. After the addition of methylene chloride, the organic phase is extracted by shaking with 15% aqueous citric acid solution and 8% aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation under reduced pressure. After chromatography of the residue over silica gel with toluene/ethyl acetate (4:1), the title compound is obtained in the form of a colourless, viscous oil. Rf (toluene/ethyl acetate 1:1): 0.29; [α]=+45± 1° (1.065% in CHCl3). The 1H-NMR spectrum (400 MHz in CDCl3) points to the existence of two rotamers in a ratio of 1:2.8.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.C(=O)([O-])[O-:17].[K+].[K+].OO.C(OCC)(=O)C>CO.CS(C)=O.O>[OH:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH2:15])=[O:17])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(c1)CCO[C@H]2CCO
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude (1S)-1-(2-hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (178 g, 0.88 mol) in methanol (460 mL) and DMSO (125 mL) was added potassium carbonate (13 g, 94 mmol). 35% hydrogen peroxide (102 mL) was then added dropwise while maintaining the temperature of the mixture below 50° C. The reaction mixture was then allowed to stir for 1 h at ambient temperature. Analysis of an aliquot by silica TLC (ethyl acetate) indicated that the reaction was complete. Water (130 mL) was added and methanol removed in vacuo. Water (800 mL) and 1N HCl (100 mL) were added and the mixture allowed to stir overnight. The solid was filtered, washed with water, and dried. Recrystallization from methyl(i-butyl)ketone gave the title compound.
Reaction SMILES: O=[C:2]1[O:6][C@H](C(Cl)(Cl)Cl)[O:4][CH:3]1[CH2:11][C:12]([OH:14])=O.S(Cl)(Cl)=O.FC(F)(F)C(O)=O.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([Cl:37])[CH:36]=1)[CH2:33][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:31][C@H:30]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47]>O.C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[C:35]([Cl:37])[CH:36]=1)[CH2:33][N:32]([CH:38]1[CH2:40][CH2:39]1)[CH2:31][C@H:30]2[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[N:47]1[C:12](=[O:14])[CH2:11][C@H:3]([OH:4])[C:2]1=[O:6]
Reactant: Nc1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Reactant: O=C(O)CC1O[C@@H](C(Cl)(Cl)Cl)OC1=O
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1C[C@H](O)C(=O)N1c1ccccc1[C@@H]1CN(C2CC2)Cc2c(Cl)cc(Cl)cc21
Yield: 20.1 %

Procedure:
Analogously to example 49, ((R)-5-oxo-2-trichloromethyl[1,3]dioxolan-4-yl)acetic acid (94 mg, see Synthesis 2002, 2165), thionyl chloride (2 ml) and 2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine trifluoroacetic acid salt (200 mg) were reacted. The freeze-drying from water/acetonitrile afforded 31 mg of the desired product.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reaction time: 4 h

Procedure:
To a round-bottom flask was added 1-(4-(6-nitropyridin-3-yl)piperazin-1-yl)ethanone 111-3 (2.6 g, 10.4 mmol), Pd/C (0.5 g) and methanol (50 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flashed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation. The crude product was purified by silica-gel flash chromatography to give 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 as an off-white solid. MS m/z 221.1 (M+1). 1H NMR 400 MHz (DMSO-d6) δ7.62 (d, 1H, J=2.8 Hz), 7.20 (dd, 1H, J1=8.8 Hz, J2=2.8 Hz), 6.41 (d, 1H, J=8.8 Hz), 5.47 (s, 2H), 3.55 (m, 4H), 2.93 (t, 2H, J=5.2 Hz), 2.86 (t, 2H, J=5.2 Hz), 2.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:11])[O:9]2)=[CH:4][C:3]=1[S:18]([Cl:21])(=[O:20])=[O:19].P(Cl)(Cl)(Cl)(Cl)[Cl:23]>ClC1C=CC=CC=1>[Cl:23][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:18]([Cl:21])(=[O:20])=[O:19])[CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:11])[O:9]1
Reactant: O=C1OC(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C1OC(Cl)(c2ccc(Cl)c(S(=O)(=O)Cl)c2)c2ccccc21

Procedure:
In a preferred procedure, 3-(4'-chloro-3'-chlorosulfonylphenyl)phthalide (17.15 g) and phosphorous pentachloride (104 g.) is heated under reflux for 2.5 hours in 300 ml of chlorobenzene. The cooled solution is extracted three times with 100 ml portions of water, dried (Na2SO4), filtered, and concentrated under a reduced pressure to give a yellow oil from which the title compound can be fractionally crystallized.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[Cl:19])[C:6]([NH2:10])=[N:7][C:8]=1[NH2:9])=[O:2].[BH4-].[Na+].O>C(O)C>[OH:2][CH2:1][C:3]1[N:4]=[C:5]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[C:12]=2[Cl:19])[C:6]([NH2:10])=[N:7][C:8]=1[NH2:9]
Reactant: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1nc(N)c(-c2cc(Cl)cc(Cl)c2Cl)nc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-Formyl-2,6-Diamino-3-(2,3,5-trichlorophenyl)pyrazine (0.198 g, 6.24×10−4 mole) in ethanol (100 ml) was added sodium borohydride (0.0359, 9.35×10−4 mole) at room temperature. The reaction was stirred at room temperature under nitrogen for 1 hr, water (1 ml) was added and the solution evaporated in vacuo. The residue was dissolved in ethyl acetate (200 ml), washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The product was purified by ‘flash chromatography’ using 11-40% ethyl acetate in cyclohexane as the eluent. Yield 0.104 g (52%), M.p. 185-186° C. N.m.r. (D6DMSO) δ: 4.32 (2H, d), 4.98 (1H, t), 5.56 (2H, s), 5.85 (2H, s), 7.30 (1H, d), 7.76 (1H, d).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][CH2:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CCCCC1
Product: CC(C)(C)c1c(NC(=O)CCC2CCCCC2)nn2cccnc12

Procedure:
The product from Example 105B and 3-cyclohexylpropionyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81-0.93 (m, 2H), 1.05-1.31 (m, 4H), 1.44-1.52 (m, 11H), 1.57-1.78 (m, 5H), 2.24-2.35 (m, 2H), 6.99 (dd, J=6.7, 4.0 Hz, 1H), 8.48 (dd, J=4.0, 1.6 Hz, 1H), 8.92 (dd, J=6.9, 1.8 Hz, 1H), 9.66 (s, 1H); MS (DCI) m/z 329 (M+H)+; EA calculated for C19H28N4O: C, 69.48; H, 8.59; N, 17.06. Found: C, 69.41; H, 8.33; N, 16.89.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:27])[C@H:19]1[C@H:23]2[CH2:24][CH2:25][C@@H:20]1[C:21](=[O:26])[CH2:22]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH3:27])[C@H:19]1[C@H:23]2[CH2:24][CH2:25][C@@H:20]1[C@H:21]([OH:26])[CH2:22]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@H]2CC[C@@H]1C(=O)C2
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCCCCCCCCO[Si](C)(C)C(C)(C)C)[C@H]1[C@H]2CC[C@@H]1[C@H](O)C2

Procedure:
To a solution of (1S,4S,7S)-7-{[9-(tert-butyldimethylsilanyloxy)nonyl]methylamino}-bicyclo[2.2.1]heptan-2-one (4.11 g, 10.4 mmol max) in dry THF (41 mL) at −5° C. under a nitrogen atmosphere was added lithium tri-tert-butoxyaluminum hydride (3.44 g, 13.5 mmol). After 1.5 h at −5° C. more lithium tri-tert-butoxyaluminum hydride (2.64 g, 10.4 mmol) was added. After 1 h at −5° C. the reaction was quenched with satd ammonium chloride solution (aq) and partitioned between ethyl acetate and water. The solids were removed by filtration and washed with ethyl acetate. The phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with satd NaHCO3 (aq), brine, dried (Na2SO4), filtered, and concentrated to dryness to afford a turbid yellow oil. The crude product was purified by column chromatography over silica gel using a gradient of 7.5-10% MeOH/DCM as eluent. After evaporation of the volatiles a light yellow/brown viscous oil was obtained.