Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH:36]=[O:37])C.[C:38](#N)C>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36]5[O:37][CH2:38][CH2:33][N:34]=5)[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C=O
Reactant: CC#N
Product: Nc1ncnn2c(C3CCCN(C4=NCCO4)C3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 3 h

Procedure:
5-(2-Benzyl-2H-indazol-6-yl)-7-piperidin-3-yl-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (63 mg, 0.15 mmol) was dissolved in 1 mL of acetonitrile and 0.5 ml. DMF and treated with 2-bromoethyl isocyante (0.013 mL, 0.16 mmol) and the mixture was stirred 3 h. The reaction was quenched by the addition of −0.2 mL water. This mixture was directly injected on to a preparative HPLC. The product containing fractions were collected, and the TFA from the eluate was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The MeOH was removed and the residue was dried overnight in a vacuum oven at 40° C. to provide the title compound. NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.91 (s, 1H), 7.80 (d, 1H), 7.59 (s, 4H), 7.38-7.24 (m, 5H), 7.12 (d, 1H), 6.61 (s, 1H), 5.62 (s, 2H), 4.24 (m, 2H), 4.10 (dd, 1H), 3.83 (dd, 1H), 3.61 (m, 2H), 2.93 (m, 1H), 2.89 (m, 1H), 2.08 (m, 1H) 1.72 (m, 2H), 1.58 (m, 1H). ES-MS m/z 493.2 [M+H]+, HPLC RT (min) 2.29.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:24][C:23](=O)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:5][C:6]1[N:7]=[C:8]([N:21]2[CH2:24][C:23]3([O:4][CH2:1][CH2:2][O:3]3)[CH2:22]2)[C:9]2[CH2:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:10]=2[N:11]=1
Reactant: OCCO
Reactant: O=C1CN(c2nc(Cl)nc3c2CCC3c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Clc1nc2c(c(N3CC4(C3)OCCO4)n1)CCC2c1ccccc1

Procedure:
Azetidin-3-one was reacted with Preparation G in the manner of Preparation Gi to afford 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one. LC-MS (M+H)+=300.0 A mixture of ethylene glycol (119 μL, 2.135 mmol), 1-(2-chloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)azetidin-3-one (320 mg, 1.068 mmol) and 4-methylbenzenesulfonic acid, H2O (20.31 mg, 0.107 mmol) in Benzene (2965 μL) was heated at reflux for 24 h in a Dean-stark apparatus. The resulting mixture was concentrated and purified by Prep-HPLC to afford the title compound. LC-MS (M+H)+=344.0. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21-7.40 (m, 3 H) 7.15 (d, J=7.63 Hz, 2 H) 4.35-4.53 (m, 4 H) 4.23 (dd, J=9.00, 6.26 Hz, 1 H) 4.03 (s, 4 H) 2.96-3.09 (m, 1 H) 2.80-2.96 (m, 1 H) 2.51-2.70 (m, 1 H) 2.03-2.16 (m, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:23]1[S:27][C:26]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:25][CH:24]=1.O1CCOCC1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:23]2[S:27][C:26]([S:28](=[O:30])(=[O:29])[NH2:31])=[CH:25][CH:24]=2)[CH:6]=1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2ccc(S(N)(=O)=O)s2)c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (272 mg, 0.33 mmol), 3-methoxycarbonylphenylboronic acid (898 mg, 4.99 mmol), and tripotassium phosphate (1.41 g, 6.64 mmol) were added to a solution of commercially available 5-bromothiophene-2-sulfonamide (805 mg, 3.33 mmol) in mixture of 1,4-dioxane (10 mL) and DMF (1 mL), followed by stirring at 85° C. overnight in an argon atmosphere. The reaction solution was concentrated. A saturated aqueous solution of sodium chloride was added to the residue, followed by extraction with methylene chloride and drying over anhydrous sodium sulfate. The solvent was distilled off, and methanol was added to the residue. The precipitated solid was filtered off. The residue obtained by distilling the solvent off was subjected to purification by silica gel column chromatography to obtain 3-(5-sulfamoyl-2-thienyl)benzoic acid methyl ester (529 mg, 1.78 mmol) (yield: 53%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CN(C)C=O.O>[CH3:24][C:23]([CH3:26])([O:22][C:20]([CH2:19][NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)=[O:21])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.6 %

Procedure:
To a solution of 2-aminonaphthalene (985 mg, 6.8 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added potassium carbonate (1.806 g, 13.6 mmol) and tert-butyl bromoacetate (1.4 mL, 9.9 mmol). The resulting reaction mixture was stirred at ambient temperature. After 24 hours, the reaction mixture was diluted with water (200 mL), then extracted by ethyl acetate (150 mL). The organic layer was separated and washed with water (3×100 mL), then dried over sodium sulfate. The solvent was evaporated in vacuo to afford a product as ann yellow oil. Purification of product by flash column on silica gel afforded 2-((1,1-dimethylethoxycarbonyl)methyl)aminonaphthalene (1.2 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][Si:9]([C:12]#[CH:13])([CH3:11])[CH3:10].[Cl:14][C:15]1[CH:16]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:18]=[N:19][CH:20]=1>C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:14][C:15]1[CH:20]=[N:19][CH:18]=[C:17]([C:13]#[C:12][Si:9]([CH3:11])([CH3:10])[CH3:8])[CH:16]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cncc(Cl)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
Sequentially add triethylamine (16 mL, 114 mmol), trimethylsilyl acetylene (4.5 mL, 34.1 mmol), bis(triphenylphosphine)palladium (II) dichloride (0.538 g, 0.77 mmol), and copper (I) iodide (270 mg, 1.42 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester (7.4 g, 28.4 mmol), (prepared as described in PREPARATION 25), in ethyl acetate (25 mL) under nitrogen. Heat at 60° C. for 1 h, cool to room temperature, stir for 12 h, filter through diatomaceous earth and wash with diethyl ether. Concentrate and purify the residue by silica gel chromatography, eluting with 20:80 ethyl acetate:hexanes, to give the title compound as an orange oil (5.51 g, 92%).
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([CH:12]1[CH2:13][CH2:14][CH2:15][C:10](=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CCCC1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1CCCC(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.1 h

Procedure:
To a solution of benzylmagnesiumchloride in THF (1.31 M, 393 mmol, 300 mL) CuCl (1.9 g) was added and the mixture was cooled to 0° C. The mixture was stirred for 6 min., and a solution of cyclohex-2-enone (193 mmol, 18.9 g) in THF (75 mL) was added dropwise at 0° C. over a period of 1 h. The reaction mixture was warmed to RT overnight. After cooling again to 0° C., saturated aqueous NH4Cl (450 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×500 mL). The combined org. layers were washed with saturated aqueous NH4Cl (500 mL) and dried over Na2SO4. After evaporation, the crude product was subjected to column chromatography (SiO2, EtOAc/Hept=1/19→1/9) to give two fractions of product 01-1. Fraction 1 (23.5 g, 125 mmol, 65%, yellow oil) was used in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[N:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][CH2:8][C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[N:3][CH:4]=1
Reactant: Clc1ccncn1
Reactant: C#CCCc1nc2ccccc2o1
Product: C(#Cc1ccncn1)CCc1nc2ccccc2o1
Yield: 17.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 4-chloropyrimidine (85 mg, 0.74 mmol) and 2-(but-3-ynyl)benzo[d]oxazole (127 mg, 0.74 mmol). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 32 mg (128 μmol, 17%) of 2-(4-(pyrimidin-4-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C:9]1[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:8].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]=O)=[CH:28][CH:27]=1)#[N:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:18]2[CH2:17][CH2:16][C:15]([CH2:14][O:13][C:12]3[CH:11]=[CH:10][C:9]([C:7]([O:6][CH3:5])=[O:8])=[CH:23][CH:22]=3)([OH:21])[CH2:20][CH2:19]2)=[CH:28][CH:27]=1)#[N:25]
Reactant: COC(=O)c1ccc(OCC2(O)CCNCC2)cc1
Reactant: N#Cc1ccc(CC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(OCC2(O)CCN(CCc3ccc(C#N)cc3)CC2)cc1
Temperature: 0 °C
Yield: 39.1 %

Procedure:
Acetic acid (11.5 mL) was added to a dichloromethane solution (450 mL) of the compound (17.7 g) obtained in Step 6 and the compound (19.4 g) obtained in Step 1 of Example 1 at room temperature and the mixture was stirred at the same temperature for thirty minutes. Sodium triacetoxyborohydride (56.6 g) was added to the mixture under cooling with ice-water and the mixture was stirred at the same temperature for thirty minutes and further stirred at room temperature for five hours. The solvent was removed under reduced pressure and insoluble matter (16.1 g) precipitated by adding water (250 mL) and ethyl acetate (250 mL) was collected by filtration. To the obtained insoluble matter (13.0 g) was added water (50 mL) and saturated aqueous sodium hydrogencarbonate solution (150 mL) and the residue was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was crystallized from ether-hexane to obtain the titled compound (10.3 g) as crystals. The physical data of the obtained compound accord with those of the compound of Example 3.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4]
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccccc1F)Nc1ccccc1C(=O)O
Yield: 85.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), ortho-fluoroaniline (7.48 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.62 g (85%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.54 (broad s, 1H), 12.01 (s, 1H), 8.72 (d, J=8.4, 1H), 7.93 (dd, J=8, J=1.4, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (t, J=7.6, 1H), 7.05 (dd, J=11.6, J=8.0, 1H), 6.94 (t, J=7.6, 1H), 6.58 (m, 2H), 6.37 (broad s, 1H), 3.90 (d, J=5.6, 2H); 13C NMR (DMSO-d6) δ 170.30, 169.19, 151.02 (J=238.1), 140.56, 136.00 (J=11.3), 134.20, 131.12, 124.77 (J=3.1), 122.71, 119.35, 116.80 (J=6.8), 114.52 (J=18.2), 111.81 (J=3.1), 48.23.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]([F:41])([F:40])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:39][S:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]([F:28])([F:40])[F:41])(=[O:38])=[O:37])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 2-(trifluoromethyl) benzenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (14%); 1H NMR (d6-DMSO) δ 12.49 (br s, 1H), 7.98-7.90 (m, 3H), 7.39-7.08 (m, 13H), 6.85 (d, J=8.0 Hz, 2H), 6.47 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 562 (M+H+)
Reaction SMILES: Cl.[C:2]1([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[S:13][CH:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:21]1[N:22]([CH2:30][C:31](O)=[O:32])[CH:23]=[C:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]2>>[N:21]1[N:22]([CH2:30][C:31]([N:18]2[CH2:19][CH2:20][CH:15]([C:12]3[S:13][CH:14]=[C:10]([CH2:9][CH2:8][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:11]=3)[CH2:16][CH2:17]2)=[O:32])[CH:23]=[C:24]2[C:29]=1[CH:28]=[CH:27][CH:26]=[CH:25]2
Reactant: c1ccc(CCc2csc(C3CCNCC3)n2)cc1
Reactant: O=C(O)Cn1cc2ccccc2n1
Agent: Cl
Product: O=C(Cn1cc2ccccc2n1)N1CCC(c2nc(CCc3ccccc3)cs2)CC1

Procedure:
4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is reacted analogously to Example I-63 with 2H-indazol-2-ylacetic acid (194 mg). After chromatographic purification, this gives 2-(2H-indazol-2-yl)-1-{-4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (67 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:5][N:4]([CH2:6][C:7]2[CH:8]=[C:9]([C:22]3[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH2:29])[N:23]=3)[C:10]([NH:13][C:14]3[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)=[N:11][CH:12]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(Cl)Cl>[NH2:29][C:24]1[N:25]=[C:26]([CH3:28])[N:27]=[C:22]([C:9]2[CH:8]=[C:7]([CH2:6][N:4]3[CH2:5][CH:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:3]3)[CH:12]=[N:11][C:10]=2[NH:13][C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:23]=1
Reactant: COc1ccc(Nc2ncc(CN3CC(N)C3)cc2-c2nc(C)nc(N)n2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(CN3CC(NS(C)(=O)=O)C3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.9 %

Procedure:
A solution of 4-(5-((3-aminoazetidin-1-yl)methyl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (106 mg, 0.269 mmol) and triethylamine (56.2 μL, 0.404 mmol) in DCM (2.7 mL) was treated with MsCl (20.85 μL, 0.269 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated. The crude product was purified via flash chromatography (silica gel) with 100% DCM to 6% 2 M ammonia in MeOH/DCM to give N-(1-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)azetidin-3-yl)methanesulfonamide (10 mg, 7% yield) as yellow solid. m/z (ESI, +ve ion) 472.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[C:3]([C:5]1[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:4].[Br:22]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Br:22][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:20])[Cl:21])[N:6]([CH2:10][C:11]([C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:12])[CH:7]=1
Reactant: Cc1cnc(C(=O)Cn2cccc2C(=O)C(Cl)(Cl)Cl)cn1
Reactant: O=C1CCC(=O)N1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)Cn2cc(Br)cc2C(=O)C(Cl)(Cl)Cl)cn1
Reaction time: 8 h
Yield: 49.2 %

Procedure:
To a solution of 2,2,2-trichloro-1-{1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}ethanone (260 mg, 0.75 mmol) in THF (4.4 mL) was added N-bromosuccinimide (144 mg, 0.81 mmol) at −15° C. The mixture was allowed at room temperature overnight. A saturated aqueous solution of NH4Cl (5 mL) was added and the mixture extracted with CH2Cl2 (3×5 mL). The organics were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that was purified by chromatography (Biotage SP4, gradient 1 CV hexanes, 0-40% EtOAc in hexanes 15 CV, 40-60% 5CV) to give 1-{4-bromo-1-[2-(5-methylpyrazin-2-yl)-2-oxoethyl]-1H-pyrrol-2-yl}-2,2,2-trichloroethanone as a yellow solid (157 mg, yield: 49%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)[CH3:3].[O-:19][C:20]#[N:21].[Na+].FC(F)(F)C(O)=O.O>C1C=CC=CC=1>[NH2:21][C:20]([O:1][CH:2]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)[CH3:3])=[O:19]
Reactant: CC(O)c1cc2c3ccccc3n(C)c(=O)n2n1
Reactant: N#C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: CC(OC(N)=O)c1cc2c3ccccc3n(C)c(=O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3.7 g (0.0172 mole) of 2-(1-hydroxyethyl)-6-methylpyrazolo[1,5-c]quinazolin-5(6H)-one in 30 ml of benzene there is added 2.6 g (0.036 mole) of solid, 90% sodium cyanate followed by the dropwise addition of 3.1 ml (0.041 mole) of trifluoroacetic acid. The reaction mixture is stirred on a magnetic stirrer at approximately 120 revolutions per minute for 2 hours at room temperature. By the end of this time a gum separates. The reaction mixture is subsequently treated with 15 ml of water with increased stirring speed after which a solid (insoluble in either phase) forms. This is filtered, washed with water and air dried to give 2.9 g (60% direct yield), m.p. 216°-221°. The solid is twice crystallized from chloroform-methanol (1:1) to give 2.0 g of analytically pure material, m.p. 250°-252°.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:28]1C=CC=CC=1)([C:22]1C=CC=CC=1)[O:6][CH2:7][CH:8]([NH:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9](O)[CH2:10]C)([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:35].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CN(C)C=O.O>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:28])[O:6][CH2:7][C@@H:8]([NH:13][C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH:10]=[O:35])([CH3:1])[CH3:3]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CCCCCCC(=O)NC(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(O)CC
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC(=O)N[C@@H](CC=O)CO[Si](C)(C)C(C)(C)C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
A mixture of (10c), (2.30 g, 6.94 mmol) and pyridinium dichromate (10.62 g, 28.2 mmol) in 20 mL of N,N-dimethylformamide is stirred under argon for 18 h. The reaction mixture is diluted with 100 mL of water and extracted with ethyl acetate (3×40 mL). The organic layer is separated, washed with water and brine, dried and evaporated to give 1.87 g of a residual brown liquid. The liquid is purified by chromatography using 1:6 ethyl acetate/hexane to give 997 mg of the desired product as an oil. NMR δ0.83 (S, 9H), 1.61 (m, 2H), 2.22 (t, 2H), 2.23 (s, 3H), 3.82 (dd, 1H), 4.09 (dd, 1H), 4.57 (m, 1H), 6.42 (brd, 1H); MS (FAB) m/z 330 (M+H calc'd for C17H36NO3Si 330).
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Cl:15])[CH:14]=1)[O:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:16](Cl)([Cl:18])=[S:17]>C(N(CC)CC)C>[Cl:15][C:13]1[CH:12]=[C:5]([CH:4]=[CH:3][C:14]=1[Cl:1])[O:6][CH:7]1[CH2:11][CH2:10][N:9]([C:16]([Cl:18])=[S:17])[CH2:8]1
Reactant: Cl
Reactant: S=C(Cl)Cl
Reactant: Clc1cc(Cl)cc(OC2CCNC2)c1
Solvent: CCN(CC)CC
Product: S=C(Cl)N1CCC(Oc2ccc(Cl)c(Cl)c2)C1

Procedure:
3-(3,5-Dichlorophenoxy)pyrrolidine hydrochloride in a solvent mixture with excess tri-ethylamine is reacted with thiophosgene to give the title compound. The triethylamine hydrochloride by-product is removed by filtration and the product isolated by evaporating off excess solvent and triethylamine.
Reaction SMILES: C(N(CC)CC)C.I[CH2:9][C:10]([NH2:12])=[O:11].[C:13]1([C:19]2[C:20]3[N:21]([CH2:36][CH2:37][N:38]=3)[C:22]3[C:27]([N+:28]=2[O-:29])=[CH:26][CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:23]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[O-:29][N+:28]1[C:27]2[C:22](=[CH:23][C:24]([N:30]3[CH2:35][CH2:34][N:33]([CH2:9][C:10]([NH2:12])=[O:11])[CH2:32][CH2:31]3)=[CH:25][CH:26]=2)[N:21]2[CH2:36][CH2:37][N:38]=[C:20]2[C:19]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Reactant: NC(=O)CI
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=O)CN1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
Triethylamine (0.75 g, 0.0072 mol.) was added to a solution of iodoacetamide (0.59 g, 0.0032 mol.) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1.0 g, 0.0029 mol.) in ethanol (50 ml) and the reaction mixture stirred overnight at room temperature. The resulting precipitate was removed by filtration, washed with ethanol and then ether. Recrystallization from ethanol yielded 2-[4-(1,2-dihydro-5-oxido-4-phenylimidazo[1,2-a]-quinoxalin-8-yl)piperazinyl]acetamide, (0.63 g) as bright yellow crystals, m.p. 225°-227° C. (Found: C, 63.50; H, 5.89; N, 19.72%; C22H24N6O6.O.75H2O requires C, 63.23; H, 6.11; N, 20.12%) represented by the structural formula: ##STR32##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9](=O)[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21]3)[CH:17]=[CH:16][C:15]=2[N+:31]([O-])=O)=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C1COCC1.O.[Fe].CC(O)=O>[O:12]=[C:11]1[CH2:10][C:9]([C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[N:31][C:15]2[CH:16]=[CH:17][C:18]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21]3)=[CH:19][C:14]=2[NH:13]1
Reactant: N#Cc1cccc(C(=O)CC(=O)Nc2cc(-n3ccc(-c4ccccc4)c3)ccc2[N+](=O)[O-])c1
Agent: [Fe]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#Cc1cccc(C2=Nc3ccc(-n4ccc(-c5ccccc5)c4)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from 3-(3-cyano-phenyl)-N-[2-nitro-5-(3-phenyl-pyrrol-1-yl)-phenyl]-3-oxo-propionamide (Example M12) by reductive cyclization with Fe/HOAc in THF/H2O at 80° C. according to the general procedure J (method d). Obtained as a yellow solid (11 mg).