Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].Cl.[CH3:16][O:17][NH2:18].[CH2:19](N(CC)CC)C>>[N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH3:19])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:18][O:17][CH3:16])([O-:3])=[O:2]
Reactant: CCN(CC)CC
Reactant: CON
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: CCc1cc([N+](=O)[O-])c(NOC)c([N+](=O)[O-])c1

Procedure:
Following the same general procedure of Example 2 and using 21.6 g. (0.1 mole) of 2,6-dinitro-4-methylchlorobenzene, 12.5 g. (0.15 mole) of methoxyamine hydrochloride, and 25.25 g. (0.25 mole) of triethylamine, the following additional compound was prepared:
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[Na+].[N+:6]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=O)[CH2:16]2)=[CH:11][CH:10]=1)([O-:8])=[O:7].BrBr.[NH2:22][C:23]([NH2:25])=[S:24].C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:6]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]3[NH:22][C:23]([NH:25][C:1](=[O:4])[CH3:2])=[SH:24][C:16]=32)=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: CC(=O)[O-]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: NC(N)=S
Agent: BrBr
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC1=[SH]C2=C(CCc3ccc([N+](=O)[O-])cc32)N1
Temperature: 15 °C

Procedure:
0.8 g (10.0 mmol) sodium acetate and 1.9 g (9.40 mmol) 7-nitro-3,4-dihydro-1H-naphthalen-2-one (prepared according to D. E. Nichols et al., J. Med. Chem. 1989, 32, 2128-2134) are dissolved in 40 ml acetic acid and cooled to 15° C. 0.5 g (3.19 mmol) bromine are added and the mixture is stirred for 0.1 hours, until the bromine has finished reacting completely. Then 0.8 g (10.5 mmol) thiourea are added. The reaction mixture is heated to 60° C. for 0.25 hours, then suction filtered and washed. The crystals are recrystallised from ethanol. Yield: 0.75 g (M.p.: 247-248° C.) 0.75 g (3.0 mmol) of the compound described previously are placed in 5 ml (49 mmol) acetic anhydride and refluxed for 0.1 hours. After cooling to ambient temperature the precipitate formed is suction filtered, washed with ethyl acetate and diethyl ether and dried. Yield: 0.8 g (M.p.: >315° C.)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl-]>O>[C:2]1([NH:1][C:9](=[O:8])[CH2:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Nc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Product: CCCC(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
First, 16 g of aniline, 200 mL of tetrahydrofuran (THF), 26 g of triethylamine (Et3N) were put in a 500 mL three-neck flask, and stirred under cooling in ice. Then, a mixed solution of 18 g of btyryl chloride and 50 mL of THF was dripped to the above mixed solution through a 100 mL dropping funnel. After the dripping, the mixture was stirred for 2 hours while the temperature was increased to room temperature. After the stirring, the reaction mixture was added to 200 mL of water, and stirred at room temperature. This mixed solution was separated to an organic layer and an aqueous layer, and the aqueous layer was extracted with chloroform. The extract and the previously resulting organic layer were combined, and washed with saturated saline. After the washing, anhydrate magnesium sulfate was added to the organic layer for drying. The mixture after the drying was subjected to gravity filtration, and the filtrate was concentrated to give a solid. This solid was washed with a mixed solvent of chloroform and hexane, so that N-phenylbutyramide was prepared (a white solid, yield: 92%). The synthetic scheme of Step 1 is shown by (a-7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.CN(C=O)C.[H-].[Na+].[C:49](OC(=O)C)(=[O:51])[CH3:50]>O.CCOC(C)=O.[Cl-].[Na+].O>[C:49]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[C:18]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[O:40][CH3:41])[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:17]=2)[N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:14]1)(=[O:51])[CH3:50]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)N(C(C)=O)CCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A vial was charged with 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.045 g, 0.072 mmol) and DMF (0.719 mL). Sodium hydride (60% in mineral oil) (4.31 mg, 0.108 mmol) was added to give a dark brown solution. Acetic anhydride (0.014 mL, 0.144 mmol) was added dropwise, and the mixture lightened significantly and thickened up. After stirring for 30 minutes at room temperature, additional acetic anhydride (0.014 mL, 0.144 mmol) was added and the reaction was heated to 50° C. and stirred for one hour. Additional sodium hydride (60% in mineral oil) (4.31 mg, 0.108 mmol) and acetic anhydride (0.014 mL, 0.144 mmol) were added and the reaction was stirred at 70° C. for one hour. The mixture was diluted with water and EtOAc, then with brine to break up an emulsion. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic extracts were combined, dried over sodium sulfate, and concentrated. The material was purified via silica gel chromatography (12 g column, gradient elution 0 to 100% EtOAc:Heptane) to afford 4-acetyl-1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a white solid. m/z (ESI) 667.7 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N-]>ClCCl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Rh+3].[Rh+3]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
To a mixture of N-benzyloxycarbonyl-4-hydroxypiperidine (2.4 g, preparation described by Alig, L. et al (1992), J. Med. Chem. 35, 4393), dirhodium tetraacetate (40 mg) and dichloromethane (15 ml) under argon was added dropwise over 3-4 hours, with stirring, a solution of ethyl diazoacetate (1.2 ml) in dichloromethane (2.5 ml). On completion of the addition, the reaction mixture was stirred at ambient temperature overnight and then evaporated. The resultant oily residue was purified by column chromatography on silica eluting with 30% ethyl acetate/hexane to give ethyl N-(benzyloxycarbonyl)piperidin-4-yloxyacetate (2.4 g) as a colourless oil: NMR Spectrum (CDCl3) 1.20 (3H, t), 1.40 (2H, m), 1.82 (2H, m), 3.13 (2H, m), 3.57 (1H, m), 3.70 (2H, m), 4.11 (2H, q), 4.13 (2H, s), 5.07 (2H, s), 7.35 (5H, m); Mass Spectrum m/Z 322 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33].C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:35][C:28]1[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([F:25])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nccc(Cl)c2cc1NC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])c(F)c3)c2cc1NC(=O)OCc1ccccc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 8.8 %

Procedure:
(4-Chloro-7-methoxyquinolin-6-yl)carbamic acid benzyl ester (1.58 g) was added to 1-methyl-2-pyrrolidone (5 ml), and then 3-fluoro-4-nitrophenol (0.87 g) and N,N-diisopropylethylamine (1.2 ml) were added and the mixture was heated and stirred at 130° C. for 6 hours. The reaction solution was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The organic layer was concentrated and the obtained residue was subjected to NH silica gel column chromatography for elution with a solvent (ethyl acetate) to obtain the title compound (188 mg) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:2]1.[CH3:28][N:29]([CH2:31][C:32](O)=[O:33])[CH3:30].C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:32](=[O:33])[CH2:31][N:29]([CH3:30])[CH3:28])[CH2:2]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: CN(C)CC(=O)O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)CN(C)C)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of [(S)-1-((R)-1-piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine from Example 16 (150 mg, 0.414 mmol), dimethylaminoacetic acid (47 mg, 0.455 mmol), HOAt (62 mg, 0.455 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (87 mL, 0.455 mmol) and 4-methylmorpholine (0.10 mL, 0.911 mmol) in anhydrous DCM (4 mL) was stirred at RT for 20 h. Volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-15% 2M NH3/MeOH in DCM) then triturated with diethyl ether affording 134 (55 mg, 30%). LCMS: RT 1.79 min [M+H]+ 448.1. 1H NMR (DMSO, 400 MHz): δ 8.23-7.93 (3H, m), 7.90-7.78 (1H, m), 7.68-7.58 (1H, m), 7.21-7.12 (2H, m), 4.80-4.69 (1H, br), 4.53-4.30 (1H, m), 4.22 (0.6H, bd, J=12.25 Hz), 4.03 (0.4H, bd, J=12.25 Hz), 3.85 (0.6H, t, J=12.08 Hz), 3.44-3.26 (1.4H, t, J=12.08 Hz), 3.21-3.10 (1H, m), 2.99 (0.4H, bd, J=13.04 Hz), 2.90-2.64 (1.6H, m), 2.44-2.26 (1H, m), 2.25-2.11 (6H, m), 1.85-1.58 (5H, m), 1.13-0.97 (1H, m). Signals split due to presence of rotamers
Reaction SMILES: N[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.N([O-])=[O:13].[Na+]>O>[OH:13][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: Cc1nc(N)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(O)ccc1[N+](=O)[O-]
Yield: 79.4 %

Procedure:
A suspension of 3.0 gm (19.6 mMol) 6-amino-3-nitro-2-picoline in 50 mL water containing 3.5 mL concentrated sulfuric acid was heated to effect solution. The resultant solution was cooled to 0° C. and a solution of 2.0 gm (29.4 mMol) sodium nitrite in 10 mL water was added with vigorous stirring at a rate to maintain the reaction mixture ≤10° C. After 4 hours the reaction mixture was filtered. The solid was washed with water and dried under reduced pressure to provide 2.4 gm (80%) of the desired compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][CH:14]([F:31])[C:15]1[N:20]=[CH:19][C:18]([C:21]2([CH2:29][NH2:30])[CH2:26][CH2:25][C:24]([F:28])([F:27])[CH2:23][CH2:22]2)=[CH:17][N:16]=1>>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:21]1([C:18]2[CH:17]=[N:16][C:15]([CH:14]([F:31])[F:13])=[N:20][CH:19]=2)[CH2:26][CH2:25][C:24]([F:27])([F:28])[CH2:23][CH2:22]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Reactant: COc1cccc(C(=O)O)c1Cl
Product: COc1cccc(C(=O)NCC2(c3cnc(C(F)F)nc3)CCC(F)(F)CC2)c1Cl

Procedure:
From 2-chloro-3-methoxybenzoic acid and (1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=446.1, tR (minutes, Method F)=2.82
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:13])([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)CC)(C)C.[C:23](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[C:3]([NH:13][C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:10]([OH:12])=[O:11])[NH:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COC1=C(C)C(N)(C(=O)O)NC=C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC1=C(C)C(NC(c2ccccc2)(c2ccccc2)c2ccccc2)(C(=O)O)NC=C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.7 %

Procedure:
1.70 g of methyl 2-amino-4-methoxy-picolinic acid (compound C6) are dissolved in 44 ml of dichloromethane. Subsequently, 1.92 ml of diisopropylethylamine, 690 mg of tetrabutylammonium iodide, and 3.12 g of trityl chloride are added. The solution is stirred for 48 h at room temperature. Thereafter, the mixture is extracted three times each with 50 ml of sat sodium hydrogencarbonate solution. The organic layer is dried using sodium sulphate, filtered with suction and concentrated in vacuum. The crude product (5.38 g) is purified by chromatography (eluent: toluene/ethyl acetate 5:1) to afford 3.49 g of the title compound as a colorless oil. TSP-MS: 425.2 [MH+]. TLC: Rf=0.37 (toluene/ethyl acetate 5:1).
Reaction SMILES: C.C1C(Br)=C(Br)[NH:4]C=1C(O)=O.N([O-])=O.[Na+].[CH3:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1.[N+:26]([O-:29])([OH:28])=[O:27]>C(O)(C)C.O>[N+:26]([O-:29])([O-:28])=[O:27].[CH2:17]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]#[N:4])=[CH:21][CH:20]=1)[CH3:16]
Reactant: CCOc1ccc(N)cc1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(Br)c(Br)[nH]1
Agent: C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCOc1ccc([N+]#N)cc1
Product: O=[N+]([O-])[O-]

Procedure:
A carbon black with a CTAB surface area of 350 m2 /g and a DBPA of 120 ml/100 g was used. A suspension of 50 g of this carbon black was prepared by stirring it into 450 g of water that contained a few drops of isopropanol. A solution of 5.12 g of NaNO2 in 15 g of cold water was slowly added to a solution of 8.40 g of p-phenetidine and 11.88 g of concentrated nitric acid in 10 g of water that was cooled in an ice bath. 4-Ethoxybenzenediazonium nitrate was formed. After 15 minutes of stirring, the mixture was added to the stirring carbon black suspension. Bubbles were released. After 30 minutes, the product was collected by filtration, washed twice with water and dried in an oven at 125° C. The carbon black product had attached p-C6H4OC2H5 groups.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:43][CH:42]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 79.3 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and 4-nitro-benzoyl chloride (49.0 mg, 0.26 mmol). The reaction mixture was stirred at 25° C. for 21 h. At this time, the reaction was concentrated in vacuo. The residue was triturated with diethyl ether to afford N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-4-nitro-benzamide (73.7 mg, 79.3%) as a pale yellow solid: mp 236-238° C.; FAB-HRMS m/e calcd for C24H24N4O4S (M+H)+ 465.1596, found 465.1617.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CN.C1COCC1.[CH3:28][N:29](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:29][CH3:28])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(-c2ccc3ncnc(N)c3n2)c1

Procedure:
Following the same reaction and purification procedure, the acid 14 (50 mg, 0.18 mmol) was reacted with methyl amine 2M in THF (0.18 mL, 0.35 mmol), HATU (103 mg, 0.6 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-methylbenzamide 20. LC/MS (ESI+): m/z 280 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.59 (dd, J=10.4, 6.2 Hz, 2H), 8.49 (d, J=8.9 Hz, 1H), 8.43 (d, J=5.3 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.07 (d, J=17.7 Hz, 2H), 7.96 (d, J=7.7 Hz, 1H), 7.63 (t, J=7.8 Hz, 1H), 2.83 (t, J=24.6 Hz, 3H).
Reaction SMILES: [CH3:1]C(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.FC(F)(F)[C:43]1[N:47]2[N:48]=[C:49](N3CCC(C4C=CC(O)=CC=4)CC3)[CH:50]=[CH:51][C:46]2=NN=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:43][N:47]1[C:51]([CH2:46][CH2:1][O:38][C:35]2[CH:36]=[CH:37][C:32]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:24]=[CH:25][C:20]5[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=5)[N:22]=4)[CH2:31][CH2:30]3)=[CH:33][CH:34]=2)=[CH:50][CH:49]=[N:48]1
Reactant: Oc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1nccc1CCOc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.2 %

Procedure:
DIAD (20.73 mL, 105.27 mmol) was added dropwise to 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (32.0 g, 87.72 mmol), 2-(1-methyl-1H-pyrazol-5-yl)ethanol (prepared as described in Example 513, preparation of starting materials) (16.6 g, 131.58 mmol) and triphenylphosphine (34.5 g, 131.58 mmol) in THF (320 mL) at 0° C. under nitrogen. The resulting solution was stirred at ambient temperature for 3 days. The reaction mixture was evaporated to dryness and re-dissolved in DCM (700 mL), and the solution was washed sequentially with 2M NaOH (200 mL×2) and saturated brine (200 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, eluting with a gradient of 80 to 100% EtOAc in isohexane followed by EtOAc, then a gradient of 0 to 3% MeOH in DCM. Pure fractions were evaporated to dryness to afford 6-[4-[4-[2-(1-methyl-1H-pyrazol-5-yl)ethoxy]phenyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (28.7 g, 69.3%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.Cl[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14].[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])=[O:23])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[CH:19]1([C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][S:13]([NH:16][C:17]([NH:1][C:2]2[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=2)=[O:18])(=[O:15])=[O:14])=[O:23])[CH2:20][CH2:21]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1ccccc1C(=O)C1CC1
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(=O)C2CC2)n1
Reaction time: 0.5 h

Procedure:
A solution of 1.78 g (0.0114 mole) of 2-amino-4,6-dimethoxypyrimidine in 50 mL of methylene chloride is cooled to 0.5° C. in an ice bath and 1.0 mL (1.62 g, 0.114 mole) of chlorosulfonyl isocyanate then added to the solution. The resulting mixture is stirred for 30 minutes and a solution of 2.66 g o-aminophenyl cyclopropyl ketone (70% real, 0.0114) and 2.6 mL triethylamine (0.0187 mole) in 50 mL of methylene chloride then slowly added to the mixture. The resulting solution is stirred at ambient temperature overnight (18 hours).
Reaction SMILES: [Mg].[CH2:2]([O:9][CH2:10][C@H:11]1[CH2:16][O:15][CH2:14][C:13](=[O:17])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl-].[NH4+].C(OCC)(=O)C.Br[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1>C(OCC)C.O1CCCC1>[CH2:2]([O:9][CH2:10][C@H:11]([NH:12][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:16][O:15][CH2:14][C:13](=[O:17])[C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[C:36]([F:42])[CH:35]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)COC[C@@H]1COCc1ccccc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](COCC(=O)c1cc(F)c(F)c(F)c1)COCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (249 mg) in diethyl ether (5 mL), 1-bromo-3,4,5-trifluorobenzene (446 μL) was added dropwise at 40° C. over 10 minutes, and the reaction solution was stirred at 40° C. for one hour. This solution was added dropwise to a solution of tert-butyl (S)-3-benzyloxymethyl-5-oxomorpholine-4-carboxylate (1.1 g) in tetrahydrofuran (30 mL) at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. for one hour. A saturated ammonium chloride solution was added to the solution in small portions at −40° C., and the reaction solution was returned to room temperature. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 952 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[CH3:15][S:16][C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20]>C(#N)C>[N+:19]([CH:18]=[C:17]([S:16][CH3:15])[NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)([O-:21])=[O:20]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Yield: 63.4 %

Procedure:
A mixture of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (12.86 g, 60 mmole) [prepared by the procedure described in Belgian Pat. No. 857,388] and 1,1-bis(methylthio)-2-nitroethylene (9.91 g, 60 mmole) [prepared according to the procedure described in Chem. Ber., 100, 591 (1967) and Acta Chem. Scand., 21. 2797 (1967)] in acetonitrile (150 ml) was stirred and heated to reflux temperature under a positive pressure of nitrogen for 15.5 hours. The solvent was removed by evaporation under reduced pressure and the crude product placed on silica gel and chromatographed using a gradient elution of methylene chloride-methanol. The appropriate fractions were combined to yield the title compound (12.6 g).