Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([OH:16])=O.Cl.[NH2:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[N:4][N:3]1[C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([CH:17]=1)[C:14]([NH:20][CH2:21][C:22]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:16]
Reactant: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)O
Reactant: NCC1(O)CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ncc(=O)[nH]c2=O)cc1C(=O)NCC1(O)CCCCCC1
Yield: 41.2 %

Procedure:
A slurry of 5-(3,5-Dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-2-methyl-benzoic acid (5.0 g, 20.2 mmol), 1-aminomethyl-cycloheptanol HCl (5.4 g, 30.3 mmol), EDCl (5.8 g), and DMAP (7.4 g, 60.6 mmol) in DMF (67.3 mL) was stirred at ambient temperature for 14 hours. The reaction was then poured into 1N HCl (50 mL) and diluted with water (15 fold). The aqueous was extracted with CH2Cl2 (3×). The organics were combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a tan solid. The crude was recrystallized from CH2Cl2 to give the title compound as an off-white solid (3.1 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:19][C:20]=3[CH3:21])[CH:11]=[CH:10][C:8]=2[CH:9]=1)#[N:2].[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+].CN(C)C=O>O>[CH3:21][C:20]1[O:19][C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:17][C:16]=1[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:8]2[CH:9]=[C:5]([CH2:4][CH2:3][C:1]3[NH:30][N:29]=[N:28][N:2]=3)[O:6][C:7]=2[CH:13]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCC#N)oc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CCc3nnn[nH]3)oc2c1
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A mixture of 2-(2-cyanoethyl)-6-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzofuran (1.20 g), sodium azide (1.09 g), ammonium chloride (0.90 g) and N,N-dimethylformamide (30 ml) was stirred at 130° to 140° C. for 16 hours. The reaction mixture was poured over water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off; the residue was subjected to silica gel column chromatography. From the fraction eluted with methanol-chloroform (5:95, v/v), 5-[2-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-benzofuranyl]ethyl ]-1H-tetrazole (1.05 g, 78%) was obtained, which was then recrystallized from dichloromethane-methanol to yield colorless prisms having a melting point of 177° to 178° C.
Reaction SMILES: [O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11]1([CH3:18])[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[O:1]=[C:2]([CH2:9][CH:10]([S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:18])=[CH:12][CH:13]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: Cc1ccc(S)cc1
Reactant: C#CC(=O)CCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(SC(CC(=O)CCCC(=O)O)Sc2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 5-oxohept-6-ynoic acid 3 (1.0 g), 4-dimethylaminopyridine (DMAP, 0.87 g) and p-toluenethiol (1.77 g) dissolved in dry dichloromethane (15 mL) was stirred at room temperature for 72 h. The reaction mixture was then diluted with ethyl acetate (40 mL) and the resulting organic phase washed with acidified water (2×15 mL, made from adding 2 ml of 1N HCl to 250 ml of deionised water) and finally saturated brine (1×10 mL). Volatiles were removed under reduced pressure (rotary evaporation) to yield a reddish brown ‘sticky’ residue which was further purified using silica based flash chromatography (Silica gel 100 C18-reversed phase, Fluka cat. No. 60754). A mobile phase consisting of hexane:ethyl acetate (60:40 v:v) was used to elute the product 7, (0.32 g, TLC Rf=0.50 using a mobile phase of hexane:ethyl acetate (25:10 v/v) acidified with acetic acid). 1H NMR (400 MHz, acetone-d6): δ 1.71 (p, 2H), 2.21 (t, 2H), 2.23 (s, 6H), 2.45 (t, 2H), 2.83 (d, 2H), 4.78 (t, 1H), 7.09 (d, 4H), 7.30 (d, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10](COCC3C=CC=CC=3)[CH:9]=[C:8]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:4]=2[N:5]=[CH:6][N:7]=1.O.NN>N.CO.[Pd]>[NH2:1][C:2]1[C:3]2[NH:10][CH:9]=[C:8]([CH2:20][NH:21][C@@H:22]([C@H:25]([OH:29])[CH2:26][S:27][CH3:28])[CH2:23][OH:24])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CSC[C@@H](O)[C@@H](CO)NCc1cn(COCc2ccccc2)c2c(N)ncnc12
Agent: [Pd]
Agent: N
Agent: NN
Solvent: CO
Solvent: O
Product: CSC[C@@H](O)[C@@H](CO)NCc1c[nH]c2c(N)ncnc12
Reaction time: 1 h
Yield: 74.1 %

Procedure:
The product from Example 6.8 (0.106 g, 0.254 mmol) was dissolved in 7M NH3-MeOH solution (10 ml), Pd black (106 mg) was added followed by hydrazine hydrate (1.5 ml). The mixture was stirred for 1 h then filtered and the solvent evaporated. The residue was chromatographed on silica gel (CH2Cl2-7M NH3 in MeOH, 85:15) to give (2R,3S)-2-((4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-4-(methylthio)butane-1,3-diol (0.056 g, 74%) as a colourless solid. [α]D20 −8.4 (c, 0.695, MeOH). 1H NMR (CD3OD) 8.16 (s, 1H), 7.47 (s, 1H), 4.11 (d, j=13.6 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.84-3.74 (m, 2H), 3.64 (dd, J=11.5, 5.0 Hz, 1H), 2.81 (q, J=5.1 Hz, 1H), 2.72 (dd, J=13.6, 4.7 Hz, 1H), 2.55 (dd, J=13.6, 7.6 Hz, 1H), 2.06 (s, 3H). 13C NMR (CD3OD, referenced to the centre line of CD3OD at 49.0 ppm) δ 152.0, 150.8, 146.5, 129.1, 115.5, 114.9, 71.2, 62.5, 61.8, 42.2, 39.3, 16.0. +ESMS Found 298.1333 (M+H)+ C12H20N5O2S requires 298.1338.
Reaction SMILES: [I-].C[N+](C)(C)[CH2:4][CH:5]1[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]=2[C:6]1=[O:15].[C-:18]#[N:19].[K+]>CO.O>[O:15]=[C:6]1[CH:5]([CH2:4][C:18]#[N:19])[CH2:11][CH2:10][S:9][C:8]2[S:12][CH:13]=[CH:14][C:7]1=2
Reactant: C[N+](C)(C)CC1CCSc2sccc2C1=O
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CCC1CCSc2sccc2C1=O
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a suspension of 59.5 g of N,N,N-trimethyl-N-[(4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-yl)methyl]ammonium iodide in 400 ml of methanol is added a solution of 25.2 g of potassium cyanide in 100 ml of water with stirring at room temperature. The mixture is stirred for 1.5 hours at the same temperature, poured into 500 ml of water and then extracted with chloroform. The extract is washed with water, dried over magnesium sulfate and the chloroform is distilled off. The resulting crystals are recrystallized from ethanol to give 32 g of 4-oxo-4,5,6,7-tetrahydrothieno[2,3-b]thiepin-5-acetonitrile as white crystals, melting at 68°-70° C.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[O:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-chloropyrazine-2-carbonitrile (74 mg, 0.257 mmol), 4-(isoxazol-5-yl)aniline (60 mg, 0.375 mmol), K2CO3 (80 mg, 0.579 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg). The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-(isoxazol-5-yl)phenylamino)pyrazine-2-carbonitrile (4 mg, 0.010 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.50 mL) and aq. H2O2 (30%, 0.50 mL) were added. The mixture was stirred at room temperature for 60 min. HOAc (0.25 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (3 mg). MS 430.4 (M+H); UV 202.3, 234.0, 274.4, 331.8 nm; t 0.483 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=2[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[NH2:24][C@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[NH2:24][CH:25]1[CH2:29][CH2:28][N:27]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[C:8]=3[NH:12][C:13](=[O:22])[CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[N:3]=2)[CH2:26]1
Reactant: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC1CCN(c2ccc3c(NC(=O)CCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 100 °C
Yield: 84 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexanepropanamide (Example 90(a)) (0.24 g), (S)-3-aminopyrrolidine (0.18 g) and triethylamine (0.1 mL) were suspended in acetonitrile and heated at 100° C. in a microwave for 1 hour. The resulting precipitate was filtered and then washed with acetonitrile to give a brown solid. Purification (SiO2, methanol:dichloromethane:triethylamine 3:97:0.5) gave the title compound as a colourless solid (230 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C@@H:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][CH2:19]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C@@H:18]1([C:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)=[O:17])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(NC(=O)[C@H]2CCCc3ccccc32)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
The mixture of 2-[((S)-1,2,3,4-tetrahydro-naphthalene-1-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (69) (440 mg, 1.21 mmol) and KOH (800 mg, 14.2 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 4 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (70) as white solid (405 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[NH:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:38]3[CH2:43][CH2:42][CH:41]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:40][CH2:39]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: C1CC(N2CCOCC2)CCN1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-piperidin-4-yl-morpholine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C36H40N4O3F3Cl2 [(M+H)+] 703.2424, observed 703.2419.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[Cl:19][C:20]([Cl:24])([Cl:23])[CH2:21][OH:22]>>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([O:22][CH2:21][C:20]([Cl:24])([Cl:23])[Cl:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: OCC(Cl)(Cl)Cl
Product: O=C(OCC(Cl)(Cl)Cl)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.0 g (0.0069 mol) of 3-(α,α, α-trifluoro-m-tolyl-4-isothiazolecarbonyl chloride and 1.22 g (1.18 equivalents) of 2,2,2-trichloroethanol was heated at 70°-140° in an oil bath for 6.5 hours. The reaction mixture was concentrated under vacuum to give 1.78 g of oil, nD23 = 1.5499 (yield 63.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH3:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([C:23](OC)=[O:24])=[N:21][CH:22]=1)(=[O:16])=[O:15].Cl>C1(C)C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23](=[O:24])[C:20]1[CH:19]=[CH:18][C:17]([S:14]([CH3:13])(=[O:16])=[O:15])=[CH:22][N:21]=1
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cn1
Reactant: Nc1ccccc1Cl
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added to trimethylaluminum (2.0 M 4.6 mL) then methyl 5-(methylsulfonyl)picolinate 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90° C. for 2 h. The reaction mixture was cooled down and 1N HCl solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2%.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[CH3:9])[C:4]([O:6][CH3:7])=[O:5].[C:17]1([S:23]([N:26]2[CH2:33][CH2:32][CH2:31][C@H:27]2[C:28](O)=[O:29])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>>[C:17]1([S:23]([N:26]2[CH2:33][CH2:32][CH2:31][C@H:27]2[C:28]([C@@:3]([NH2:2])([C@@H:8]([C:10]2[CH:11]=[CH:12][C:13]([I:16])=[CH:14][CH:15]=2)[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:29])(=[O:24])=[O:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: COC(=O)[C@@H](N)[C@H](C)c1ccc(I)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: COC(=O)[C@@](N)(C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1)[C@H](C)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To an ice cooled solution of 2(S)-amino-3(R)-(4-iodophenyl)-butyric acid, methyl ester hydrochloride (116 mg, 0.34 mmol), N-(benzenesulfonyl)-(L)-proline (128 mg, 0.50 mmol), HOBt (77 mg, 0.5 mmol) and N-methylmorpholine (55 μL, 0.5 mmol) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 99 mg, 0.5 mmol). After stirring overnight, the solvents were removed by rotoevaporation, and the residue was dissolved in methylene chloride and loaded onto a flash silica gel chromatography column. The product was eluted with 10% ethyl acetate in methylene chloride to yield 163 mg (85% yield) of the title compound.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:47]([NH:54][NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:16]([NH:55][NH:54][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:18])[CH:13]([CH3:14])[CH3:15])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 66 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-valine (0.540 g, 2.15 mmol), EDAC (0.450 g, 2.35 mmol), HOBT (0.320 g, 2.37 mmol), NMM (0.260 mL, 2.36 mmol), benzylhydrazine×2HCl (0.500 g, 2.56 mmol) and Et3N (0.710 mL, 5.09 mmol) which gave the title compound (0.502 g, 66%) as a white solid.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:33]([CH:38]([CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])[OH:39])([O:35][CH2:36][CH3:37])=[O:34]>CCOCC>[CH:18]1([CH2:17][CH2:16][NH:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:41][CH:40]([CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[OH:39])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:14])=[CH:8][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: O=C(Cl)Cc1ccc(N(CCC2CCCCC2)C(=O)C(F)(F)F)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(O)C(OC(=O)Cc1ccc(NCCC2CCCCC2)cc1)C(=O)OCC

Procedure:
A mixture of 4-[N-trifluoroacetyl-(2-cyclohexylethylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(2-cyclohexylethylamino)phenylacetyl]-tartrate as a white, crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:30]5[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=5)[CH2:38]4)=[CH:17][C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: O=[N+]([O-])c1ccc(C2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3cc(N4CCNC(c5ccc([N+](=O)[O-])cc5)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7-fluoro-1-methyl-8-[3-(4-nitrophenyl)-1-piperazinyl]-4-oxo-1,4 -dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (0.636 g) and (RS)-2-(4-nitrophenyl)piperazine (0.5 g). After recrystallization in dimethylformamide (10 cc), the expected product (0.7 g) is obtained in the form of a yellow solid, decomposing at approximately 300° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][O:12][C:13]2([CH3:17])[CH3:16])=[CH:9][CH:8]=1.[CH3:18][N:19]1[C:23]([CH:24]=[O:25])=[N:22][C:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:20]1>C1COCC1>[CH3:16][C:13]1([CH3:17])[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([CH:24]([C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:22]=3)[OH:25])[CH:15]=2)[CH2:11][O:12]1
Reactant: Cn1nc(-c2ccccc2)nc1C=O
Reactant: CC1(C)OCc2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccc2)nc1C(O)c1ccc2c(c1)C(C)(C)OC2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
BuLi (0.36 mL, 1.6 M in hexanes, 0.57 mmol) was added dropwise to a solution of Intermediate 388.2 (110 mg, 0.49 mmol) in THF (5 mL) at −78° C. After stirring 5 min, a solution of Intermediate 386.1 (100 mg, 0.54 mmol) in THF (3 mL) was added. The mixture was warmed to 0° C. over 2 h and quenched with sat. NH4Cl (1 mL). The mixture was diluted with H2O (20 mL) and extracted with EtOAc (3×20 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated. Purification by flash chromatography (hexanes, EtOAc) yielded 63 mg of Intermediate 388.3 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.37 (s, 6 H) 3.48 (s, 3H) 4.90 (s, 2H) 5.68 (s, 1H) 6.01 (s, 1H) 6.93-7.00 (m, 1H) 7.10-7.14 (m, 1H) 7.14-7.19 (m, 1H) 7.28-7.38 (m, 3H) 7.89-7.95 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][S:12][C:11](=[O:14])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1NN=C(c2ccc(Cl)cc2)CS1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1SCC(c2ccc(Cl)cc2)=NN1Cc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of the compound obtained in Step A (57.83 mmoles) in acetonitrile (260 ml) there are added 1-bromomethyl-4-nitro-benzene (63.61 mmoles) and potassium carbonate (231.32 mmoles). The reaction mixture is stirred at 80° C. for 1 hour under nitrogen. The reaction mixture is brought to ambient temperature and 100 ml of water are added. Extraction with ethyl ether (3×350 ml) is carried out and the organic phases are combined. The organic phase obtained is dried over sodium sulphate, filtered and evaporated to dryness. The solid is triturated in ethyl ether, filtered off and dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>>[F:13][C:14]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:2]([CH3:1])[CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:17]
Reactant: CNCCC#Cc1ccccn1
Reactant: O=C(Cl)c1cccc(F)c1F
Product: CN(CCC#Cc1ccccn1)C(=O)c1cccc(F)c1F
Yield: 72 %

Procedure:
The title compound was prepared in accordance with the general method of Example 199(D), from N-methyl-4-(pyridin-2-yl)but-3-yn-1-amine (50 mg, 0.31 mmol) and 2,3-difluorobenzoyl chloride (72 mg, 0.41 mmol). The crude residue was purified over silicagel chromatography (prepacked 10 g silicagel column, DCM/MeOH: from 100/0 to 98/2 as eluent) to afford 67 mg of 2,3-difluoro-N-methyl-N-(4-(pyridin-2-yl)but-3-ynyl)benzamide as a brown oil (Yield: 71%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(N)c1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc(C)c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
To a stirred solution of 57 mg (0.20 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) (57 mg, 0.20 mmol) in ethanol (2 ml), m-toluidine (64 mg, 0.60 mmol) was added portionwise. The resulting mixture was stirred at room temperature for 30 min and the final product was collected by filtration and washed with ethanol and diethylether to yield the title compound (24 mg, 35% yield).