Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[S:23])[N:3]1[C:24]1[CH:25]=[C:26]([C:32]([F:35])([F:34])[F:33])[C:27]([C:30]#[N:31])=[N:28][CH:29]=1.Br[CH:37]([CH3:39])[CH3:38].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>C1COCC1>[CH:37]([N:20]1[CH2:21][CH2:22][CH:17]([O:16][C:13]2[CH:14]=[CH:15][C:10]([N:5]3[C:4](=[S:23])[N:3]([C:24]4[CH:25]=[C:26]([C:32]([F:34])([F:33])[F:35])[C:27]([C:30]#[N:31])=[N:28][CH:29]=4)[C:2](=[O:1])[C:6]43[CH2:9][CH2:8][CH2:7]4)=[CH:11][CH:12]=2)[CH2:18][CH2:19]1)([CH3:39])[CH3:38]
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(OC4CCNCC4)cc3)C2=S)cc1C(F)(F)F
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCC(Oc2ccc(N3C(=S)N(c4cnc(C#N)c(C(F)(F)F)c4)C(=O)C34CCC4)cc2)CC1
Temperature: 70 °C
Yield: 9.2 %

Procedure:
To a solution of 5-(8-oxo-5-(4-(piperidin-4-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (50 mg, 0.10 mmol) in anhydrous THF (1 mL) was added 2-bromopropane (20 μL, 0.20 mmol) followed by cesium carbonate (100 mg, 0.30 mmol). The reaction mixture was heated at 70° C. overnight. DMF (1 mL) was added to improve solubility and the reaction was heated at 85° C. for 3 h. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous was extracted further with EtOAc (2×) and the combined organics were washed with water, then brine. The organics were dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC provided 5 mg of 5-(5-(4-((1-isopropylpiperidin-4-yl)oxy)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.04 (d, 1H), 8.30 (d, 1H), 7.13 (d, 2H), 6.99 (d, 2H), 4.37-4.26 (m, 1H), 2.81-2.33 (m, 10H), 2.25-1.74 (m, 5H), 1.00 (d, 6H). LCMS [M+1]+ 544.0.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([O:21]COC)=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:26])[C:9]=3[C:8]2=[O:27])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:19](=[O:20])[C:18]3[C:17]([OH:21])=[C:16]4[C:11]([CH:12]=[CH:13][CH:14]=[N:15]4)=[C:10]([O:25][CH3:26])[C:9]=3[C:8]2=[O:27])=[CH:28][CH:29]=1
Reactant: COCOc1c2c(c(OC)c3cccnc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Crude diether 8 (0.0223 g, 0.0527 mmol) was dissolved in 1 mL dichloromethane. Ten equivalents of trifluoroacetic acid was added. The mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and azeotroped with toluene (2×) to give crude 7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione 9 which was triturated with 8 mL of 1:1 diethylether/hexane and filtered to give 9 (0.0161 g, 0.0456 mmol, 83% for two steps). 1H NMR (CDCl3) δ 9.0 (br s, 1 H), 8.7 (d, 1 H), 7.7 (d, 1H), 7.5 (m, 2 H), 7.0 (t, 2 H), 4.8 (s, 2H), 4.4 (s, 3H). (M+1).
Reaction SMILES: C(OC(N[C@H:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.[C:15]([O:19][C:20]([NH:22][C@H]1CCNC1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH:14]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Product: CC(C)(C)OC(=O)NC1CCNCC1

Procedure:
3-(S)-tert-butoxycarbonylaminopiperidine (B=formula (2)) and 3-(S)-tert-butoxycarbonylaminopyrrolidine (B=formula (3)) (Synth. Comm. 1998, 28, 3919) in the last two cases Y═COOC(CH3)3; tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-exo-carbamate (B=formula (4), tert-butyl 8-azabicyclo[3.2.1]-oct-3-yl-endo-carbamate (B=formula (5)) (J. Med. Chem. 1991, 34, 656), tert-butyl 9-azabicyclo[3.3.1]-non-3-yl exo-carbamate (B=formula (6)) and tert-butyl 9-azabicyclo-[3.3.1]-non-3-yl-endo-carbamate (B=formula (7)), (J. Med. Chem. 1993, 36, 3720)) (Y═COOC(CH3)3).
Reaction SMILES: C([N-:4]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[S:21]1[C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=[CH:22]1.N(C(C1C=CC=CC=1)=C)=[N+]=[N-]>C1COCC1.CCCCCC>[NH2:4][C:22]1[S:21][C:29]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[CH:23]=1
Reactant: CC(C)[N-]C(C)C
Reactant: c1cc2sccc2cn1
Agent: C=C(N=[N+]=[N-])c1ccccc1
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Nc1cc2cnccc2s1
Temperature: -15 °C

Procedure:
To a cold (-70° C.) stirred solution of lithium diisopropylamide in THF, prepared in situ by reaction of 3.63 g of freshly distilled diisopropylamine and 22 ml of 1.6M n-butyl lithium in 50 ml of hexane, were added dropwise over twenty minutes 4.05 g (30 mMoles) of thieno[3,2-c]pyridine in 20 ml of THF. The reaction mixture was stirred for twenty minutes following the addition, and then was diluted by the dropwise addition of 5.22 g (36 mMoles) of α-azido styrene in 20 ml of THF. The reaction mixture was stirred for two hours while maintaining the temperature at -70° to -50° C.; and then for an additional hour while allowing the temperature to warm to -15° C. The reaction was then quenched by the addition of 50 ml of 5% aqueous hydrochloric acid. Removal of the reaction solvent by evaporation under reduced pressure afforded 3.0 g of crude product. Purification by chromatography over silica gel, eluting with ethyl acetate, afforded 1.2 g of 2-aminothieno[3,2-c]pyridine. Mass Spec. M+ theory: 150, found: 150.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CN(C)C(=O)C>[S:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[C:11]([CH3:13])[CH3:12])[C:3]=1[C:4]#[N:5])(=[O:17])(=[O:16])[NH2:15]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)=Cc1cccc(N)c1C#N
Solvent: CC(=O)N(C)C
Product: CC(C)=Cc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 2-amino-6-(2-methylprop-1-enyl)benzonitrile (Example 129b) (1.24 g; 7.23 mmol) in N,N-dimethylacetamide (DMA) (20.0 mL), under a nitrogen atmosphere, was treated with sulfamoyl chloride (1.67 g; 14.45 mmol) at room temperature. The obtained mixture was stirred at room temperature for 2 h and the reaction was quenched with water (40 mL). The mixture was extracted with EtOAc (4×80 mL), the combined extract was washed with water (2×20 mL) and brine, and dried with MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using gradient (Hexanes/EtOAc 1:0 to 1:1), to give 1.69 g (93%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.42 (broad s, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.24 (broad s, 2H), 7.19 (d, J=8.0 Hz, 1H), 6.35 (broad s, 1H), 1.92-1.95 (m, 3H), 1.76-1.79 (m, 3H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccnc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccnc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
Under a dry nitrogen atmosphere a solution of 12.0 ml (0.096 mole) of phenyl chloroformate in 300 ml of methylene chloride was added dropwise to a cold (0° C.) stirred solution of 10.2 g (0.079 mole) of 4-amino-2-chloropyridine and 16.5 ml (0.12 mole) of triethylamine in 300 ml of methylene chloride. After complete addition the reaction mixture was allowed to come to room temperature and stirred at room temperature for approximately 18 hours. The mixture was washed with three 100 ml portions of water followed by 100 ml of an aqueous saturated sodium chloride solution. The washed mixture was dried over anhydrous magnesium sulfate and filtered. The filtrate was subjected to column chromatography on silica gel, eluted with acetone:methylene chloride (4:96), to yield 7.4 g of phenyl N-(2-chloro-4-pyridinyl)carbamate as a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]3[C:17]([N:18]4[CH2:23][CH2:22][O:21][CH:20]([CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19]4)=[N:16][CH:15]=[N:14][C:10]=3[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].C(Cl)Cl>CO>[C:29]([O:28][C:26]([NH:25][CH2:24][CH:20]1[O:21][CH2:22][CH2:23][N:18]([C:17]2[C:9]3[C:8]4[C:12](=[CH:13][C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=4)[NH:11][C:10]=3[N:14]=[CH:15][N:16]=2)[CH2:19]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1ncnc(N3CCOC(CNC(=O)OC(C)(C)C)C3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(=O)O)ccc4c23)CCO1
Reaction time: 8 h

Procedure:
A suspension of 4-[2-(tert-Butoxycarbonylamino-methyl)-morpholin-4-yl]9H-pyrimido[4,5-b]indole-7-carboxylic acid methyl ester (35 mg, 0.079 mmol) in methanol (2 mL) was treated with NaOH (1 mL, 4 M in dioxane, 4 mmol) and left overnight at room temperature. DCM (5 mL) was added to the reaction mixture. The aqueous layer was collected and acidified with 1M HCl, evaporated to dryness and suspended in water. The resulting precipitate was collected by filtration as a white solid (12 mg, 0.028 mmol). LC-MS (1) Rt 1.17 min; m/z (ES−) 426.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:29]=[CH:28][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=3)=[CH:28][CH:29]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc([N+](=O)[O-])cc3)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)NCc2ccc(Cc3ccc(N)cc3)cc2)cc1
Reaction time: 6 h
Yield: 87.9 %

Procedure:
4-[4-(4-Methoxyphenyl)sulfonylaminomethylbenzyl]-nitrobenzene (791 mg) was dissolved in ethyl acetate (15 mL) and hydrogenated over 5% palladium on carbon at room temperature. The reaction was allowed to proceed for 6 hours, filtered, and evaporated to dryness. The crude product thus obtained was chromatographed on a short silica column, eluting with hexane/ethyl acetate (1:1), to give 4-[4-(4-methoxyphenyl)sulfonylaminomethylbenzyl]-phenylamine (645 mg, 87%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:37][CH:38]1[CH2:40][O:39]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][N:12]([CH2:37][CH:38]([OH:39])[CH3:40])[N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[S:22][CH:23]=2)[N:3]=1
Reactant: CC1CO1
Reactant: N#Cc1c(N)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(O)Cn1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccc(Cl)cc4)n3)c2C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10 mg (0.022 mmol) of 2-amino-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 1 ml of 2-methyloxirane, and a spatula tip of cesium carbonate was added. The reaction mixture was stirred at room temperature overnight, concentrated, taken up in a little methanol and purified by preparative HPLC (acetonitrile/water: 10:90→95:5, 0.1% TFA added). This gave 10 mg (86% of theory) of the target compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][C:5]=1[O:30][CH3:31])([CH3:3])=[CH2:2]>[Pd].C(O)C>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:29])=[C:16]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][CH2:11]2)=[CH:6][C:5]=1[O:30][CH3:31])([CH3:3])[CH3:2]
Reactant: C=C(C)c1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1OC
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Yield: 92.8 %

Procedure:
A mixed solution of N-(3-(4-isopropenyl-3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.93 g, 4.58 mmol) obtained in Example 184 and 10% palladium on carbon (water content: 50%, 193 mg) in ethanol (10 mL) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated to give 1.80 g (yield: 93%) of the title compound. Melting point: 170-171° C. (ethyl acetate-hexane).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH2:16])=[N:14][CH:15]=1>CC#N>[Br:8][C:12]1[C:13]([NH2:16])=[N:14][CH:15]=[C:10]([F:9])[CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(F)cn1
Solvent: CC#N
Product: Nc1ncc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.4 %

Procedure:
NBS (10 g, 56.2 mmol) was added slowly to a solution of 5-fluoro-pyridin-2-ylamine (12.4 g, 56.2 mmol) in MeCN (200 mL). The reaction mixture was stirred at RT overnight. After completion, the solution was filtered and the filtrate was concentrated to get a residue, which was purified by silica gel chromatography to give the product (5.2 g, 31%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][C:9]=2[O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH:11]=[N:10][C:9]=2[O:15][CH2:16][C:17]([F:18])([F:20])[F:19])=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)n1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 48e, using 6-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyrazin-2-ylamine (example 49d) and nicotinoyl chloride hydrochloride as starting materials; LC-MS (UV peak area/ESI) 95.7%, 407.0532 (M−H)−.
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[N:11]=[C:5]2[N:4]=[CH:3]1.[C:19]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:24])[CH2:20][CH2:21][C:22]#[CH:23].C(N(CC)CC)C.O>CN(C)C=O.[Cu]I>[OH:8][C:7]1[N:2]([C:23]#[C:22][CH2:21][CH2:20][C:19]([NH:25][C@H:26]([C:33]([O:35][CH3:36])=[O:34])[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:24])[CH:3]=[N:4][C:5]2=[N:11][C:10]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:6]=12
Reactant: CC(C)(C)C(=O)Nc1cc2c(O)n(I)cnc-2n1
Reactant: C#CCCC(=O)N[C@@H](CCC(=O)OC)C(=O)OC
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC[C@H](NC(=O)CCC#Cn1cnc2nc(NC(=O)C(C)(C)C)cc-2c1O)C(=O)OC
Reaction time: 2 h

Procedure:
To a mixture of 3.6 g (10 mmol) of well-dried 3-iodo-4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidine in 40 mL of dimethylformamide are added 4.0 g (13.19 mmol) of dimethyl N-(pent-4-ynoyl)-L-glutamate, 0.38 g of copper (I) iodide, 3 mL of triethylamine, and 1.0 g of tetrakis-(triphenylphosphine)palladium. This mixture is stirred at ambient temperatures for two hours and then poured into 500 mL of water. The solid is collected by filtration, air dried, and then refluxed in 200 mL of methanol. The mixture is cooled and the solid collected by filtration, dissolved in two liters of 10% methanol in methylene chloride, and chromatographed over silica. Initial black bands are rechromatographed and the combined colorless bands from the first and second runs are evaporated to give dimethyl N-[5-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d] pyrimidin-3-yl)pent-4-ynoyl]-L-glutamate which can be purified further by recrystallization from 50% methanol in methylene chloride.
Reaction SMILES: CN1CCN=C1C1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:34])[CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:18])=CC=1.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50]C=2N=N1>CN(C=O)C>[N:42]1[CH:46]=[CH:47][C:48]([N:13]2[CH2:10][CH2:11][CH:11]([CH2:10][NH:13][C:14](=[O:34])[CH:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH3:33])[NH:16][C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)=[O:18])[CH2:12][CH2:14]2)=[CH:49][CH:50]=1
Reactant: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)Nc1ccc(C2=NCCN2C)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1C(NC(=O)Nc1ccc(Cl)cc1)C(=O)NCC1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 2-(2-methylphenyl)-2-(4-chlorophenylaminocarbonylamino)-acetic acid (from EXAMPLE 84, 30 mg, 0.094 mmol), 4-[1-(pyridin-4-yl)piperidinyl]methylamine hydrochloride (36 mg, 0.19 mmol) and TEA (0.052 mL, 0.37 mmol) in DMF (3 mL), BOP (62 mg, 0.14 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (15 mg). MS 492.4 and 494.4 (M+H, Cl pattern).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl[C:14]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:17]=[C:16]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:15]=1.O>CN(C=O)C>[NH2:1][C:2]1[N:6]([C:14]2[N:19]=[C:18]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:17]=[C:16]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2n1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
9.32 g (70 mmol) of 2-aminobenzimidazole dissolved in DMF (300 ml) was added and reacted with 60% sodium hydride (2.80 g, 70 mmol) at room temperature for 30 minutes. This suspension was added to a solution of 14.3 g (50 mmol) of 2-chloro-4,6-dimorpholino-1,3,5-triazine dissolved in DMF (200 ml) and stirred at room temperature for 2 hours. The reaction solution was poured into water and the resulting precipitates were washed with water and methanol to obtain 17.7 g (yield: 93%) of 2-(2-aminobenz-imidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine. (2) 0.38 g (1.0 mmol) of 2-(2-aminobenzimidazol-1-yl)-4,6-dimorpholino-1,3,5-triazine and 0.24 g (4.0 mmol) of acetic acid were added to and further 0.83 g (4.0 mmol) of DCC was added to chloroform (5 ml) and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The separated organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to obtain 0.31 g (yield: 73%) of the titled compound as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[Br-].Br[CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.O>CN(C)C=O.C(OCC)(=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: BrC1CCCC1
Reactant: Oc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1ccccc1OC1CCCC1
Temperature: 120 °C
Yield: 95.3 %

Procedure:
A mixture of 2-iodophenol (8.0 g, 36.4 mmol), milled potassium carbonate (5.5 g, 39.9 mmol, 1.1 eq) and 1-bromocyclopentane bromide (3.9 ml, 36.4 mmol) in 25 ml of N,N-dimethylformamide was heated at 120° C. for 1.1 hrs and cooled. The mixture was poured into water and extracted twice with ether. The ether layer was dried over magnesium sulfate, filtered, and concentrated to give an oil. The crude product was dissolved in ethyl acetate and filtered through a short pad of silica gel. The filtrate was redried over magnesium sulfate, filtered and concentrated under vacuum to give 10 g (95%) of product as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14](Cl)[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([CH2:30][OH:31])[CH2:28][NH2:29].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([NH:29][CH2:28][CH2:27][CH2:30][OH:31])[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1NCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: OCCCNc1nc2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Yield: 84.8 %

Procedure:
A solution of N-benzyl-4-chloro-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-8-amine (30 mg; 0.079 mmol; 1 eq), 3-propanolamine (20 μl; 0.264 mmol; 3.3 eq) and diisopropylethylamine (15 μl; 0.088 mmol; 1.1 eq) in anhydrous 1,4-dioxane (0.5 ml) is stirred under argon at 100° C. for 16 h. Partition (ethyl acetate/aqueous ammonium chloride), washings of the organic phase (twice with aqueous ammonium chloride, once with brine), drying (magnesium sulfate) and concentration affords the title product (28 mg; 0.067 mmol; 86%) as a white solid.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:2]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]2[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c1ccncc12
Product: COC(=O)c1ccc2c(c1)nc(Cl)c1ccncc12
Reaction time: 2 h

Procedure:
Methyl 5-oxo-5,6-dihydrobenzo[c][2,6]naphthyridine-8-carboxylate (200 mg, 0.787 mmol) was combined with phosphorus oxychloride (1 mL) and heated to reflux. After 2 hours, LCMS indicated the absence of any starting material. The volatiles were removed under reduced pressure. The residue was taken up in dichloromethane (50 mL) and washed twice with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator to give methyl 5-chlorobenzo[c][2,6]naphthyridine-8-carboxylate (140 mg) as a grayish solid. LCMS (ESI) 273.3 (M+1)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7](=[O:18])[NH:8][CH2:9][CH2:10][S:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1CCCN1C(=O)NCCSc1ccccn1
Solvent: ClCCl
Product: O=C1CCCN1C(=O)NCCS(=O)c1ccccn1
Reaction time: 1.5 h
Yield: 43.8 %

Procedure:
To a solution of 2.0 g (7.54 mmol) of 2-oxo-1-[[2-(pyridin-2-ylthio)ethyl]carbamoyl]pyrrolidine in 35 ml of CH2Cl2 was added 1.63 g (7.54 mmol) of m-CPBA (content 80%) under ice-cooling. Then the mixture was stirred for 1.5 hr. at room temperature. The reaction solution was washed with aqueous NaHCO3 and water. After drying, the solvent was removed by evaporation. The residue was refined by silica gel column chromatography, then the crystalline objective compound was obtained from the eluate with benzene/ethyl acetate (3/1-1/1 v/v). The compound was washed with Et2O and collected by filtration, whereby 0.93 g of the crystalline compound (I b-3) melting at 119.5°-120.5° C. was obtained. Yield: 43.9%.