Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1OCC)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH3:22]>>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][CH2:12][C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:22])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOc1c(CNCCP(=O)(OCC)OCC)c(=O)c1=O
Reactant: N
Product: CCOP(=O)(CCNCc1c(N)c(=O)c1=O)OCC
Reaction time: 18 h
Yield: 77 %

Procedure:
An ethanolic solution (40 ml) of [2-[(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester (3.00 g, 9.40 mmol) was combined with ethanolic ammonia solution (70 mL) and left for 18 hours. After concentrating in vacuo, the solid was recrystallized twice from methanol in ethyl acetate (final volume=50 mL) to yield [2-[(2-amino-3,4-dioxo-1-cyclobuten-1-yl)methylamino]ethyl]phosphonic acid diethyl ester as a solid (2.10 g, 77%, mp 130°-132° C.); IR (KBr, cm-1): 3320, 3160, 1800, 1670, 1650, 1640; MS (+FAB): 291 (MH+, 100),196 (22), 109 (20); 1H NMR (DMSO, 400 MHz): δ 7.61 (br s NH2), 4.02-3.94 (m, 4H), 3.74 (br s, 2H), 3.13 (br s, 3H), 2.13 (d of t, J=18 and 7.5 Hz, 2H), 1.22 (t, J=7 Hz, 6H).
Reaction SMILES: ClC1C=CC2N(C(CNC3N=C(N4CCC(C)(O)CC4)C=CN=3)=C(C3C=CC=CC=3)N=2)C=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52](Cl)[N:51]=2)=[CH:36][CH:35]=1.[CH3:57][NH:58][NH2:59]>>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]=[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][N:43]3[C:48]=2[CH2:49][C:50]2[CH:55]=[N:54][CH:53]=[C:52]([NH:59][NH:58][CH3:57])[N:51]=2)=[CH:36][CH:35]=1
Reactant: CNN
Reactant: Clc1ccc(-c2nc3ccccn3c2Cc2cncc(Cl)n2)cc1
Agent: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Product: CNNc1cncc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the experimental for compound 187 from 2-(4-chlorophenyl)-3-((6-chloropyrazin-2-yl)methyl)imidazo[1,2-a]pyridine and methylhydrazine. M/e+ 365 for C19H18ClN6 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.12 (d, J=6.9 Hz, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.73 (s, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.19 (m, 1H), 6.78 (t, J=6.9 Hz, 1H), 4.36 (s, 2H), 3.88 (bs, 2H), 3.18 (s, 3H) ppm.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(O)[O-].[Na+].[C-]#N.[K+].CC([O:31][C:32](ON=C(C1C=CC=CC=1)C#N)=[O:33])(C)C.C(N(CC)CC)C.OS([O-])(=O)=O.[K+]>O.C(OCC)(=O)C>[C:14]([O:13][C:12]([NH:11][C@H:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:9]([OH:10])[C:32]([OH:33])=[O:31])=[O:18])([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)CC1CCCCC1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: O=S([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Example 3B (19.7 g, 77.1 mmol) and sodium bisulfite (8.0 g, 77.1 mmol) in water (500 mL) at 5° C. was stirred for 24 hours, warmed to room temperature, treated with a solution of potassium cyanide (5.1 g, 78.8 mmol) in ethyl acetate (350 mL), and stirred for 5 hours. The aqueous phase was separated and extracted with ethyl acetate. The combined extracts were washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was dissolved in dioxane (150 mL), treated with 12M HCl (150 mL), heated to reflux, stirred for 21 hours, and cooled to room temperature. The mixture was concentrated, dissolved in a mixture of water (30 mL) and acetone (200 mL), adjusted to pH 5.5 with 1M NaOH, treated with acetone (3.5 L), and cooled to 0° C. for 4 hours. The resulting precipitate was collected by filtration. The filter cake was dried, dissolved in 1:1 water/dioxane, treated with BOC-ON (1.2 eq.), and triethylamine (2 eq.), heated to 45° C., stirred for 15 hours, treated with 10% aqueous KHSO4, and extracted with ethyl acetate. The extract was washed sequentially with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][C:6](=[O:25])[N:5]([CH3:26])[C:4]1=[O:27].[C:28](=[O:31])([O-])[O-].[K+].[K+]>O>[CH3:2][N:3]1[C:8]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:31][CH3:28])=[CH:18][CH:17]=2)=[CH:7][C:6](=[O:25])[N:5]([CH3:26])[C:4]1=[O:27]
Reactant: Cn1c(NCCNCCCc2ccc([N+](=O)[O-])cc2)cc(=O)n(C)c1=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc(CN(CCCc2ccc([N+](=O)[O-])cc2)CCNc2cc(=O)n(C)c(=O)n2C)cc1

Procedure:
1.4 g of 1,3-dimethyl-6-{2-[3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione hydrochloride (Compound e) were dissolved in 5 ml of water, followed by the addition of potassium carbonate to render the solution alkaline. The solution was then extracted with chloroform. The thus-obtained chloroform solution was concentrated to dryness, followed by the addition of 0.6 g of p-methoxybenzyl bromide, 3 ml of triethylamine and 20 ml of isopropanol. The resultant mixture was heated for 8 hours under reflux. The solvent was distilled off under reduced pressure and the residue was directly subjected to chromatographic purification on a silica gel (eluent: chloroform/methanol=40/1, by volume), thereby obtaining 0.55 g of 1,3-dimethyl-6-{2-[N-(4-methoxybenzyl)-3-(4-nitrophenyl)propylamino]ethylamino}-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69].[BH4-].[Na+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [BH4-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reaction time: 20 h

Procedure:
To a solution of {4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 7) (0.025 g, 0.049 mmol) and NMM (0.020 ml, 0.178 mmol) in DMF (3 ml) at RT was added TBTU (0.020 g, 0.062 mmol). The reaction mixture was stirred for 90 min after which glycyl-3-cyclohexyl-D-alanine (Method 9) (0.012 g, 0.035 mmol) was added. The mixture was stirred for 20 h before the reaction was quenched by the addition of water (1 ml). The mixture was diluted with methanol (2 ml) and then NaBH4 (0.028 g, 0.740 mmol) was added. After 15 min the reaction was quenched by the addition of an aqueous solution of hydrochloric acid (1M, 1 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as.
Reaction SMILES: Br[C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:17]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[C:31]1(B(O)O)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[C:31]1([C:2]2[C:3]3[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:9]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[O:23][C:24]5[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=5[N:26]=4)=[CH:20][CH:21]=3)=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reactant: OB(O)c1cccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: c1ccc2c(-c3c4ccccc4c(-c4ccc(-c5nc6ccccc6o5)cc4)c4ccccc34)cccc2c1
Yield: 78.4 %

Procedure:
In a 50 mL three-neck flask, 0.90 g (2.0 mmol) of 2-[4-(10-bromo-9-anthryl)phenyl]benzoxazole, 0.37 g (2.2 mmol) of 1-naphthaleneboronic acid, 0.50 g (4.7 mmol) of sodium carbonate, 10 mL of toluene, 3 mL of ethanol, and 3 mL of water were placed. The mixture was degassed by being stirred under reduced pressure, and the air in the flask was replaced with nitrogen. To the mixture, 32 mg (0.027 mmol) of tetrakis(triphenylphosphine)palladium(0) was added, and the mixture was stirred under nitrogen stream at 80° C. for 7 hours. After a certain period, water was added to the mixture, and an aqueous layer was extracted with toluene. The obtained extracted solution and the organic layer were combined and washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and the organic layer was dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. The solid was purified by silica gel column chromatograghy (toluene:hexane=2:1) and recrystallized with toluene/hexane, giving 0.78 g of the target pale yellow powder in a yield of 78%.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[CH2:5]1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:38](OCC)(=[O:44])[C:39](OCC)=[O:40]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:4]3[C:1](=[O:3])[CH:2]=[C:38]([OH:44])[C:39]([OH:40])=[C:5]3[C:6]2=[O:22])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)N1CC(=O)N(Cc2ccc(F)cc2)c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1c2c(O)c(O)cc(=O)n2c2ccccc2n1Cc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of 4-acetyl-1-(4-fluorobenzyl)-3,4-dihydro-quinoxalin-2(1H)-one (0.15 g, 0.52 mmol) in DMF (5 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (0.57 mL, 0.57 mmol) was added and stirred at the temperature for 30 min. The resultant solution was treated with diethyl oxalate (0.078 mL, 0.57 mmol), and stirred at room temperature overnight. The resultant mixture was then treated with additional lithium bis(trimethylsilyl)amide in THF (1.6 mL, 1.6 mmol) and stirred at room temperature for 6 h. The product mixture was concentrated under vacuum, and the residue partitioned between aqueous HCl and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound as white solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:12]([O:16][C:17](=[O:24])[NH:18][C@H:19]1[CH2:22][C@H:21](O)[CH2:20]1)([CH3:15])([CH3:14])[CH3:13].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>C1COCC1.C([O-])(O)=O.[Na+]>[C:12]([O:16][C:17](=[O:24])[NH:18][C@H:19]1[CH2:20][C@H:21]([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[N:2]([CH3:1])[C:3]2=[O:11])[CH2:22]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: Cn1c(=O)[nH]c2ncccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n([C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)c2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (9.63 g, 64.6 mmol), tert-butyl(trans-3-hydroxycyclobutyl)carbamate (Intermediate 69, 12.1 g, 64.6 mmol), and triphenylphosphine (25.4 g, 97 mmol) were mixed in THF (250 mL) under an argon atmosphere at 0° C. Diisopropyl azodicarboxylate (19.0 mL, 97 mmol) was added dropwise via syringe, and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was diluted with saturated NaHCO3 and extracted with EtOAc (3×). The organic layer was separated, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting crude product was purified via silica gel flash column chromatography eluting with 0 to 100% EtOAc in hexanes to yield the title compound as a yellow solid and used in the next step without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[N:18]=[CH:17][N:16]=[C:15]2[C:11]=1[NH:12][CH:13]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:23]1[O:39][C:38]([CH2:46][O:47][S:48]([CH3:51])(=[O:50])=[O:49])([CH2:40][O:41][S:42]([CH3:45])(=[O:44])=[O:43])[C@@H:29]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]1[O:25][C:26](=[O:28])[CH3:27])(=O)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:26]([O:25][C@@H:24]1[C@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]([CH2:46][O:47][S:48]([CH3:51])(=[O:50])=[O:49])([CH2:40][O:41][S:42]([CH3:45])(=[O:43])=[O:44])[O:39][C@H:23]1[N:18]1[C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:11]2[C:15](=[N:14][CH:13]=[N:12]2)[N:16]=[CH:17]1)(=[O:28])[CH3:27]
Reactant: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reactant: CC(=O)OC1OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cnc3ncnc-3c2NC(=O)c2ccccc2)OC(COS(C)(=O)=O)(COS(C)(=O)=O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
6-N-Benzoyladenine (11.02 g.; 46.1 mmol) was dried in vacuo overnight. 1,2-Di-O-acetyl-3-O-benzyl-4-C-methanesulfonyloxymethyl-5-O-methanesulfonyl-D-ribofuranose (19.6 g.; 38.4 mmol) (3) was coevaporated in anh. acetonitrile (3×50 mL) and dried in vacuo overnight. 3 was redissolved in anh. 1,2-dichloroethane (stored over molecular sieves) (175 mL), 6-N-Benzoyladenine was added followed by N,O-bistrimethylsilylacetamide (25.1 mL; 101.3 mmol). The mixture was refluxed for 1 h and cooled to rt. TMS-triflate (13.9 mL; 76.8 mmol) was added and the mixture was refluxed for 5h, stirred overnight at rt, refluxed for further 24 h (red-brown solution) and cooled to rt. The solution was poured into an ice-cold saturated aqueous solution of NaHCO3 (200 mL) and stirred for 0.5 h. The precipitate was filtered off, the phases were separated and the organic phase was washed with a saturated aqueous solution. of NaHCO3 (3×150 mL), dried (Na2SO4) and evaporated. Purification by silica gel column chromatography (1-1.5% MeOH in CH2Cl2) gave 4D as a slightly yellow solid in 68% yield (18.0 g.). NMR was consistent with the data reported in an earlier patent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:19]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH2:18][Cl:19])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc2c(-c3ccc(Cl)cc3)nccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1cccc2c(-c3ccc(Cl)cc3)nccc12
Yield: 79.9 %

Procedure:
To 100 ml of carbon tetrachloride was added 14 g of 1-(4-chlorophenyl)-5-methylisoquinoline. While the solution was heated under reflux and light was irradiated on it, 7.5 g of N-chlorosuccinimide was added. The mixture was heated with stirring. After the reaction, the reaction mixture was cooled. The insoluble matter was removed by filtration. The filtrate was washed in water, and dried, followed by distilling off the solvent. Recrystallization of the residue from ether-hexane afforded 12.7 g of 1-(4-chlorophenyl)-5-chloromethylisoquinoline as light yellow prisms having a melting point of 101° to 102.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[Cl-].[Li+].N12CN=CC1CCCC2.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)([CH:36]=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(#N)C>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33]([CH:38]2[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]2)([CH:36]=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:32][CH2:31]1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(C2CCCCC2)CC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: C1=NCN2CCCCC12
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Product: COC(=O)C=CC1(C2CCCCC2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of trimethyl phosphonoacetate (1.41 ml, 8.72 mmole), lithium chloride (477 mg, 11.3 mmole), and 1,8-diazabicyclo[4.3.0]non-7-ene (DBU) (1.55 ml, 11.3 mmole) in anhydrous acetonitrile (25 ml) is added 4-cyclohexyl-4-formyl-piperidine-1-carboxylic acid tert-butyl ester, 7, (2.58 mg, 8.72 mmole) under argon at room temperature. The mixture is stirred for one hour and the solvent then removed under reduced pressure. The crude product is purified over silica (methylene chloride:methanol=15:1, Rf=0.78) to afford 2.64 g (86% yield) of the desired compound.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]([CH3:22])=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23]C)[CH:18]=4)[N:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1>CN1C(=O)CCC1>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]([CH3:22])=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([OH:23])[CH:18]=4)[N:13]=3)=[CH:8][CH:7]=2)=[N:1][N:2]=[N:3]1
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Solvent: CN1CCCC1=O
Product: Cc1cc2cc(O)ccc2nc1-c1ccc(-c2nnn[nH]2)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
2-(4-(1H-tetrazol-5-yl)phenyl)-6-methoxy-3-methylquinoline (128 mg, 0.40 mmol) was dissolved in 5 mL of NMP and Na2S (47 mg, 0.60 mmol) was added to it. The mixture was then stirred for 4 hours at 140° C. in a microwave reactor. After concentration in vacuo the crude was dissolved in 5 mL of 1N NaOH and slowly acidified with 1N HCl to a pH of 4. The solids were filtered and dried in vacuo to afford 46.2 mg (38% yield) of Compound IV-2. 1H NMR (DMSO-d6, 400 MHz): δ 10.10-10.00 (bs, 1H), 8.18-8.15 (d, 2H), 8.08 (s, 1H), 7.87-7.84 (m, 3H), 7.30-7.26 (d, 1H), 7.13 (s, 1H), 2.45 (s, 3H). MS (ESI): m/z 304.11 [M+H]+.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[Li+].[Cl-].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(C)=O.CCO>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[N:11][CH:12]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(Cl)cc2)cn1
Temperature: 25 °C

Procedure:
The trifluoromethane sulfonate from Step 1 (500 mg) was dissolved in 10 mL of toluene, 5 mL of EtOH, and 1.6 mL of 2M aqueous Na2CO3. Then 203 mg LiCl, 411 mg of 4-chlorobenzeneboronic acid (Lancaster) and 832 mg of tetrakis (triphenylphosphine) palladium were added successively. The resulting reaction mixture was heated up to 90°-95° C. for 1 hour. The reaction mixture was cooled down to room temperature, EtOAc was added, and the organic phase was washed with 1N NaOH, brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography using hexane: EtOAc 3:2 gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH3:16])[C:12]([OH:14])=O.[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>>[C:18]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH3:16])=[CH:21][CH:20]=1)#[N:17]
Reactant: COc1cc(F)c(C(OC)C(=O)O)c(F)c1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1cc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Light yellow amorphous solid. MS 347.1 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN6CCN(C)CC6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure for Example 72 from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide and 1-methylpiperazine. MS (ES+APCI) m/z=523 (M+H) detected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)[CH:9]=1)[C:5]#[N:6].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C=O)C>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[CH:19]=2)[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(N)cc(Oc2cncnc2)c1
Reactant: O=C(O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(NC(=O)c2cccc(F)c2)cc(Oc2cncnc2)c1
Yield: 42.2 %

Procedure:
Compound 22 (10 mg, 0.047 mmol, 1.2 eq), 3-fluorobenzoic acid (5.5 mg, 0.039 mmol, 1.0 eq), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (31 mg, 0.082 mmol, 2.1 eq), and N,N-Diisopropylethylamine (11 mg, 0.085 mmol, 2.1 eq) were dissolved in CH2Cl2 (0.43 mL) and DMF (0.09 mL) and stirred at rt overnight. The reaction was quenched with water, and the layers were separated via phase separation. The organic layer was dried on air concentrator and purified by flash chromatography on silica gel to give 5.5 mg (42%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 9.08 (s, 1H), 8.57 (s, 2H), 8.13 (s, 1H), 7.80 (s, 1H), 7.74 (s, 1H), 7.59 (dd, J=18.9, 8.4 Hz, 2H), 7.51-7.46 (m, 1H), 7.31-7.26 (m, 1H), 7.08 (s, 1H); ES-MS [M+1]+: 335.1.