Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH2:14])[CH2:3][CH2:2]1.[C:15](Cl)(=[O:17])[CH3:16]>>[CH:1]1([C:4]2[CH:9]=[C:8]([F:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[NH:14][C:15](=[O:17])[CH3:16])[CH2:3][CH2:2]1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Reactant: CC(=O)Cl
Product: CC(=O)Nc1cc([N+](=O)[O-])c(F)cc1C1CC1
Yield: 84 %

Procedure:
The general procedure described in Example 51 was followed. N-(2-Cyclopropyl-4-fluoro-5-nitrophenyl)acetamide (2.04 g, 84%) was obtained from 2-cyclopropyl-4-fluoro-5-nitrobenzenamine (described in WO2011068898) and acetyl chloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[H-].[Na+].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13]>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: OCc1cccs1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccs1
Reaction time: 0.25 h
Yield: 48.9 %

Procedure:
To a stirring 25 mL solution of 1.14 g (10 mmol) of thiophenemethanol in THF was added 0.24 g (10 mmol) of NaH. After the evolution of gas had ceased, 1.53 g (10 mmol) of methyl bromoacetate was added to the reaction. After 15 minutes, the reaction mixture was filtered. The solvent was removed under reduced pressure. The residue was then dissolved in 50 mL of EtOAc. The organic layer was washed with 3×50 mL of H2O, and was treated in the manner described above in Example 7. The residue was chromatographed to yield 0.91 g (49%) of product. Analysis calculated for C8H10O3S (M.W. 186.23): C, 51.60; H, 5.41. Found: C, 51.41; H, 5.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.C([O-])(=O)C.[Na+].[I:22]Cl>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[O:6][C:7]2[C:13]([I:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: ClI
Reactant: COC(=O)Nc1nc2c(OC)cccc2o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(I)c2o1
Reaction time: 30 h
Yield: 65.4 %

Procedure:
To a stirred solution of 40 g (18 mmol) (4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester and 4.4 g (54 mmol) sodium acetate in 20 ml acetic acid at room temperature was added dropwise 8.8 g (54 mmol) iodine monochloride and stirring continued for 30 h. The mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were washed with 1 M aqueous sodium thiosulphate solution, then dried over sodium sulfate and concentrated in vacuo. Trituration in ether afforded 4.1 g (65%) (7-iodo-4-methoxy-benzooxazol-2-yl)-carbamic acid methyl ester as a white crystalline solid. ES-MS m/e (%): 349 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([F:9])([F:8])[F:7])C.O.[NH2:12][NH2:13]>>[F:7][C:6]([F:9])([F:8])[CH2:5][C:4]([NH:12][NH2:13])=[O:3]
Reactant: CCOC(=O)CC(F)(F)F
Reactant: NN
Solvent: O
Product: NNC(=O)CC(F)(F)F

Procedure:
Ethyl-3,3,3-trifluoropropanoate (2.5 g, 0.016 mol) and hydrazine monohydrate (1.2 g, 0.024 mol) were heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was treated with toluene (100 ml×3) to azeotrope hydrazine in excess.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1>>[N:23]1([CH2:22][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[N:24]1
Reactant: ClCn1nnc2ccccc21
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cn2nnc3ccccc32)c1
Yield: 26.6 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 1-chloromethyl-1H-benzotriazole were reacted by the same way with the example 1 to obtain the titled compound (108 mg, yield: 26.6%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([NH2:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:29][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:22])[CH2:20][CH2:19]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC3CC3)c(C3CC3)cn2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (13 mg, 23%) as colorless oil; MS (ESI, m/z): 383.6 (M+H+)
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: COc1ccc(CCN2CCC[C@@H](Cl)C2)cc1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 289.5 %

Procedure:
Sixty-percent sodium hydride (480 mg, 12 mmols) was washed with petroleum ether, and then suspended in 40 ml of dimethyl sulfoxide. To the suspension were added 2.0 g (10 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 30 minutes. To this reaction solution was added dropwise a solution of 8.8 g (35 mmols) of (R)-(-)-3-chloro-1-(4-methoxyphenethyl)piperidine [[α]D25 =-7.4 (c=1.1, ethanol)] in 30 ml of dimethyl sulfoxide at room temperature, and the mixed solution was stirred for 90 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 12.0 g of (S)-(-)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 80%.
Reaction SMILES: [C:1]([C:3](=[C:9]1[CH2:14][CH2:13][CH:12](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[BH4-].[Na+]>C(O)C.O>[C:1]([CH:3]([C@H:9]1[CH2:14][CH2:13][C@H:12](/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCC/C=C/C1CCC(=C(C#N)C(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCC/C=C/[C@H]1CC[C@H](C(C#N)C(=O)OCC)CC1
Temperature: 5 °C
Reaction time: 0.75 h

Procedure:
A solution of 46.0 g of ethyl cyano-[4-(1E-pentenyl)cyclohexylidene]acetate in 120 ml of ethanol is added dropwise at 5°-10° C. within 40 minutes to a mixture of 6.7 g of sodium borohydride and 120 ml of ethanol. The reaction mixture is stirred at 5° C. for 45 minutes, then diluted with 750 ml of water and extracted with three 250 ml portions of diethyl ether. The extract is washed neutral with water, dried over sodium sulphate and concentrated. There is obtained crude ethyl cyano-[trans-4-(1E-pentenyl)cyclohexyl]acetate (cis content <20%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=3[N:8]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[CH2:30]([N:15]1[C:14]2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][CH3:19])[C:11](=[O:20])[N:10]([CH2:21][CH2:22][CH3:23])[C:9]=2[N:8]=[C:7]1[CH:4]1[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: CCCn1c(=O)c2[nH]c(C3CCC(=O)C3)nc2n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(C3CCC(=O)C3)n2Cc2ccccc2)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
10.0 g (0.031 mol) of 8-(3-oxocyclopentyl)-1,3-dipropyl-7H-purine-2,6-dione are dissolved in 30 ml of absolute dimethylformamide and after the addition of 4.6 g (0.033 mol) of potassium carbonate the mixture is stirred for 20 minutes at ambient temperature. 5.7 g (0.033 mol) of benzylbromide are added dropwise, the mixture is stirred for a further 40 minutes and the reaction is ended by the addition of water. The solution is evaporated down, the residue is taken up in water and extracted with dichloromethane. After drying and evaporation, the combined organic phases yield an oily residue which is purified on silica gel with a mixture of dichloromethane/methanol in the ratio 99:1 and then recrystallised from ethanol. 9.4 g (73.3% of theory) of the title compound are obtained in the form of colourless crystals, melting point: 145° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([Li])CCC.[CH3:18][O:19][CH2:20][C:21](N(OC)C)=[O:22]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:21](=[O:22])[CH2:20][O:19][CH3:18])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COCC(=O)N(C)OC
Agent: [Li]CCCC
Product: COCC(=O)c1ccc(OC)cc1C(=O)O

Procedure:
This compound is synthesized according to the method described in 3.2. by reacting 2-bromo-5-methoxybenzoic acid pretreated with n-butyllithium with 2,N-dimethoxy-N-methylacetamide. It is used in crude form in the following reaction.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([C:31]1[S:35][C:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:33][CH:32]=1)(=[O:30])=[O:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:39]2[CH2:38][CH2:37][N:36]([C:34]3[S:35][C:31]([S:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)(=[O:30])=[O:29])=[CH:32][N:33]=3)[CH2:41][CH2:40]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: O=S(=O)(c1ccccn1)c1cnc(N2CCNCC2)s1
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(S(=O)(=O)c3ccccn3)s2)CC1)C(F)(F)F
Yield: 68 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-[5-(pyridine-2-sulfonyl)-thiazol-2-yl]-piperazine hydrochloride (Example 45(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 68%). MS (m/e): 605.0 (M+H+, 100%).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([C:16]2[CH:17]=[N:18][C:19]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:21]=2[C:22]#[N:23])=[CH:11][C:10]=1[S:28](=[O:38])(=[O:37])[N:29]([CH3:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:13]1[C:12]([C:16]2[CH:17]=[N:18][C:19]([C:24]([F:27])([F:25])[F:26])=[CH:20][C:21]=2[C:22]#[N:23])=[CH:11][C:10]([S:28](=[O:38])(=[O:37])[N:29]([CH3:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:9]([CH:14]=1)[O:8][CH2:7][C:6]([OH:39])=[O:5]
Reactant: CN(c1ccccc1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ccccc1)S(=O)(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OCC(=O)O
Yield: 17.4 %

Procedure:
[5-Chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid tert-butyl ester (27 mg, 0.046 mmol) was dissolved in DCM (0.2 mL) and TFA (0.2 mL) and was stirred at r.t. for 1 h. The solvent was removed and purification by prep TLC eluting with 70% acetone/hexane gave [5-chloro-4-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid 19-1 (4 mg, 0.008 mmol). MS [M+H]+: 526.0; tR=7.98 min. (method 2)
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[CH:10][C:9]=1[CH2:20][OH:21].[Br:22]C(F)(F)C(F)(F)Br.O>C1COCC1>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH3:19])=[C:10]([Br:22])[C:9]=1[CH2:20][OH:21]
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: COc1cc(CO)c(OC)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1c(Br)c(CO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.2 %

Procedure:
n-Butyllithium (2.9 mL, 7.33 mmol, 2.5 M in hexanes) was added dropwise to a solution of 23a (400 mg, 1.83 mmol) in THF (25 mL) at −78° C. under argon. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. 1,2-dibromotetrafluoroethane (0.26 mL, 2.20 mmol) was added dropwise and the solution was stirred for 1 h. Water (10 mL) was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), filtered and evaporated. Column chromatography of the crude product (35:65 EtOAc:hexanes) afforded 23d (273 mg, 50%, 63% based on recovered 23a, 84 mg) as a yellow solid; Rf=0.62 (35:65 EtOAc:hexanes); mp=115-117° C.; 1H NMR (CDCl3): δ 8.11 (m, 2H), 7.57 (m, 2H), 5.03 (s, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 2.36 (bs, 1H).
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:6][CH:7]([NH:20][C:21](=[O:22])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:8][NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NC(CNC(=O)OCc1ccccc1)COS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CN=[N+]=[N-])CNC(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]propyl methanesulfonate (20.0 g, 49.7 mmol) in DMF (400 mL) was added sodium azide (8.0 g, 120 mmol). The reaction mixture was heated to 50° C. After 24 hours, the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate. The organic layers were concentrated under reduced pressure to afford benzyl tert-butyl (3-azidopropane-1,2-diyl)biscarbamate. The material was used without purification. MS ESI calc'd. for C16H24N5O4 [M+H]+ 350. found 350.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([N+:6]([O-:21])=[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]3[N:9]2[CH2:12][CH2:13][N:14]=3)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:15]1([C:7]2[C:8]3[N:9]([CH2:12][CH2:13][N:14]=3)[C:10]3[C:5]([N+:6]=2[O-:21])=[CH:4][CH:3]=[C:2]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:11]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(F)ccc21
Reactant: C1CNCCN1
Product: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Yield: 91.2 %

Procedure:
Under a nitrogen atmosphere, 1,2-dihydro-8-fluoro-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (40 g 0.142 mol) and piperazine (122 g, 419 mol) were heated at 9° C., for 3.5 hrs. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over anhydrous magnesium sulphate and concentrated in vacuo to yield an orange solid. The orange solid was recrystallized from chloroform-ethyl acetate to yield 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide, (45 g) as orange crystals, m.p. 209°-211° C. (Found: C, 68.56; H,6.06; N,19.99%; C20H21N5O.O.2H2O requires C, 68.43; H,6.14; N,19.95%) represented by the structural formula: ##STR24##
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)[N:9]=1)[C:2]([NH2:4])=[NH:3].[OH-].[Na+].Cl>O.C(O)C>[NH:1]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1nc(CCCCN2C(=O)c3ccccc3C2=O)c[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(N)Nc1nc(CCCCN)c[nH]1

Procedure:
To a solution of 2-guanidino-4-(4-phthalimidobutyl)imidazole (0.25 g.) in water/ethanol 1:1 v/v (20 ml.) was added sufficient dilute sodium hydroxide solution to give a pH of 12. The mixture was heated under reflux for 30 minutes, the pH adjusted to 3 with concentrated hydrochloric acid, the mixture heated under reflux a further 30 minutes and then cooled. The pH was readjusted to 12 with sodium hydroxide solution and then the total mixture evaporated to dryness to give crude 2-guanidino-4-(4-aminobutyl)imidazole which was used without further purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([O:20][CH3:21])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:16]3[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=3[O:20][CH3:21])=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(I)ccc1O
Reactant: OCc1ccc(C2CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(I)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 46.5 %

Procedure:
To a solution of (4-cyclopropylphenyl)methanol (4.5 g) prepared in (2) and 4-iodo-2-methoxyphenol (7.5 g) in THF (40 mL) were added triphenylphosphine (8.7 g) and diisopropyl azodicarboxylate (6.5 mL) at 0° C. The reaction mixture was stirred at RT for 22 hr. The solvent was removed under reduced pressure. The residue was purified by silica-gel chromatography (Developing solvent: hexane/ethyl acetate=9/1) to give the title compound (5.3 g, 46%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][N:14]=[C:13]4[NH2:19])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[NH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[C:9]4[C:4]=3[CH2:3][C:2](=[O:22])[NH:1]4)[CH:11]=2)[NH:15][N:14]=1
Reactant: CCO
Reactant: Nc1n[nH]c2ccc(-c3cccc4[nH]ccc34)cc12
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: Nc1n[nH]c2ccc(-c3cccc4c3CC(=O)N4)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To the suspension of 5-(1H-indol-4-yl)-1H-indazol-3-ylamine (0.82 g, 3.33 mmol) in t-BuOH:ethanol:acetic acid (20.5 mL:12 mL:6 mL) was added pyridinium tribromide (3.17 g, 9.9 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, it immediately became a dark pink color. Zinc dust (excess) was added to the reaction mixture portionwise. After stirring for one hour, the unreacted zinc was filtered off and the solvent was removed under reduced pressure. The residue was washed with ample of water. The solid was triturated with DCM to give 0.563 g (77%) of 4-(3amino-1H-indazol-5-yl)-1,3-dihydro-indol-2-one.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[O:5][CH3:6].[OH:16][CH:17](C1OC=CC=1)C1C=CC=CC=1OC>>[CH3:6][O:5][CH:4]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[O:16][CH3:17]
Reactant: COc1ccccc1C(O)c1ccco1
Reactant: COC(c1ccco1)c1ccccc1Cl
Product: COc1ccccc1C(OC)c1ccco1

Procedure:
(±) 2-(α,2-Dimethoxybenzyl)furan (b.p. 112°-115° C./0.1 mm.Hg) was prepared in a manner similar to that described in Example 3(k) for the preparation of (±) 2-(2-chloro-α-methoxybenzyl)furan but replacing the (±) 2-(2-chloro-α-hydroxybenzyl)furan by (±) 2(α-hydroxy-2-methoxybenzyl)furan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:15])[C:12]([O-:14])=O.[K+].[C:17]([N:25]1[CH2:30][CH2:29][NH:28][C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:17]([N:25]1[CH2:30][CH2:29][N:28]([C:12](=[O:14])[C:11]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][N:5]=3)[NH:9][CH:8]=2)=[O:15])[C@H:27]([CH3:31])[CH2:26]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])C(=O)c1c[nH]c2c(Cl)ccnc12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Agent: [K+]
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2c(Cl)ccnc12

Procedure:
Precursor 5d, 1-benzoyl-3-(R)-methyl-4-[(7-chloro-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from Potassium (7-chloro-4-azaindol-3-yl)-oxoacetate, Precursor 4e, and 1-benzoyl-3-(R)— methyl piperazine. MS m/z: (M+H)+ calcd for C21H20ClN4O3 411.12, found 411.04. HPLC retention time: 1.10 minutes (column A).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1.Br[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1>>[CH3:1][O:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])[S:7][CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: COCc1csc(NC(=O)c2nc(C)ccc2N)n1
Product: COCc1csc(NC(=O)c2nc(C)ccc2Nc2cc(F)cc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methoxymethyl-thiazol-2-yl)-amide in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-bromopyridine to yield the final compound as a yellow solid, MS (ISP): m/e=391 (M+H+).