Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:31]1[CH2:36][CH2:35][N:34]([CH2:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:33][CH2:32]1.C([O-])([O-])=O.[Na+].[Na+].O1CCO[CH2:61][CH2:60]1.O>O.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>[CH2:29]([N:22]([CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)[C:4]1[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH2:17][CH2:60][CH3:61])=[O:8])[CH:20]=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([CH2:37][N:34]3[CH2:35][CH2:36][O:31][CH2:32][CH2:33]3)=[CH:43][CH:42]=2)[CH:3]=1)[CH3:30]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: C1COCCO1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(CN3CCOCC3)cc2)cc(N(CC)C2CCOCC2)c1C
Temperature: 100 °C
Yield: 70 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.3 g, 0.59 mmol) and 4-((morpholino)methyl)phenylboronicacid pinacol ester (0.22 g, 0.71 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.23 g, 2.14 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (0.068 g, 0.059 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.25 g, 70%). LCMS: 601.55 (M+1)−; HPLC: 97.21% (@210-370 nm) (Rt; 4.380; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (bs, 1H), 8.16 (bs, 1H), 7.57 (d, 2H, J=7.6 Hz), 7.38 (t, 3H, J=6.8 Hz), 7.21 (s, 1H), 5.89 (s, 1H), 4.30 (m, 2H), 3.84-3.82 (m, 2H), 3.57 (bs, 3H), 3.48 (s, 3H), 3.3.8-3.22 (m, 2H), 3.09-3.02 (m, 3H), 2.36 (bs, 4H), 2.25 (s, 3H), 2.11 (s, 3H), 1.67-1.54 (m, 6H), 0.93 (t, 3H, J=7 Hz), 0.84 (t, 3H). 2H merged in solvent peak.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+](C1C=CC([C:27](Cl)=[O:28])=CC=1)([O-])=O.[CH3:32][S:33]([C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[N:41]([C:45]1[CH:50]=[C:49]([O:51][CH:52]3[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]3)[N:48]=[CH:47][N:46]=1)[CH2:40][CH2:39]2)(=[O:35])=[O:34]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:27]([N:55]2[CH2:56][CH2:57][CH:52]([O:51][C:49]3[CH:50]=[C:45]([N:41]4[C:42]5[C:38](=[CH:37][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:44][CH:43]=5)[CH2:39][CH2:40]4)[N:46]=[CH:47][N:48]=3)[CH2:53][CH2:54]2)=[O:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCNCC2)ncn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(OC(=O)N2CCC(Oc3cc(N4CCc5cc(S(C)(=O)=O)ccc54)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Hydroxy-azetidine-1-carboxylic acid tert-butyl ester (0.17 g, 1 mmol) was dissolved in 3 mL of DCM with triethylamine (0.28 mL, 2 mmol). 4-Nitro-benzoyl chloride (0.2 g, 1 mmol) was added and the mixture was stirred at room temperature for 12 h. A fifth of the solution was reacted with 4b (75 mg, 0.2 mmol). The mixture was stirred at room temperature for 8 h, diluted with DCM and washed with saturated NaHCO3. The organic layer was evaporated to afford crude 22a, LCMS 574.2 (MH+).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:12]=2[S:13][C:14]=1[C:15]([NH2:17])=[O:16].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C=O)C.C(OCC)(=O)C>[CH3:23][O:22][C:20]1[CH:19]=[CH:18][C:12]2[S:13][C:14]([C:15]([NH2:17])=[O:16])=[C:10]([S:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]=2[CH:21]=1
Reactant: COc1ccc2sc(C(N)=O)c(Cl)c2c1
Reactant: SCc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2sc(C(N)=O)c(SCc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Benzylmercaptan (134 μL, 1.14 mmol) is added to a suspension of 3-chloro-5-methoxybenzo[b]thiophene-2-carboxamide (250 mg, 1.03 mmol) in 2 mL of DMF. Diazabicycloundecene (DBU) (170 μL, 1.14 mmol) is added and the mixture is warmed to 50° C. After 1 hour, the reaction mixture is allowed to cool and then is diluted with ethyl acetate and washed with 1N NaOH, 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane gives 5-methoxy-3-[(phenylmethyl)thio]benzo[b]thiophene-2-carboxamide in 63% yield; mp=151°-153° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=3)[N:6]=2)[CH2:2]1.[CH3:17][C:18]1[N:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=3)=[N:26][C:21]2=[N:20][CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C.C(N(CC)CC)C>[CH3:17][C:18]1[N:22]2[CH:23]=[C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]([C:27]3[CH:34]=[CH:33][C:30]([CH2:31][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:29][CH:28]=3)=[N:26][C:21]2=[N:20][CH:19]=1
Reactant: Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Reactant: Cc1cccc(-c2n[nH]c(C3CNC3)n2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(C3CN(Cc4ccc(-c5nc6ncc(C)n6cc5-c5ccccc5)cc4)C3)n[nH]2)n1
Reaction time: 1 h

Procedure:
168 mg 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-6-methylpyridine×2HCl (intermediate example 44.1; 60% pure) are dissolved in 2.8 ml NMP. After addition of 0.1 ml triethylamine the reaction mixture is stirred for one hour. 100 mg (0.32 mmol) 4-(3-Methyl-6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (intermediate example 12.0) and 0.03 mL acetic acid are added and the reaction mixture is stirred overnight at room temperature. 74.4 mg (0.35 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature for 20 hours. The reaction mixture is treated with saturated NaHCO3 and the precipitate filtered off, washed with water and dried. After chromatography of the precipitate on silica gel (dichloromethane/methanol) 36.6 mg (21%) of the desired product are obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:12][CH2:13][O:14][CH3:15])[C:10]=1[Cl:11])=[O:5])C.[OH-].[Li+]>CO.O>[Cl:11][C:10]1[N:9]([CH2:12][CH2:13][O:14][CH3:15])[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(CCOC)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COCCn1ncc(C(=O)O)c1Cl
Yield: 31.4 %

Procedure:
To a solution of 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (4.60 g, 19.77 mmol) in methanol (32 mL) and water (32 mL) was added lithium hydroxide (1.10 g, 26.22 mmol). The reaction mixture was stirred at reflux for 3 h, and then the solution was concentrated under reduced pressure to remove the methanol. The residue was then acidified carefully with 6.0 N aqueous HCl. The resulting mixture was extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to provide 5-chloro-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylic acid as a white solid (1.27 g, 31%). Mass spectrum: m/z: 205.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1(/[CH:19]=[C:20](\B2OC(C)(C)C(C)(C)O2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)(C)C.O.C1(P([Pd-4](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)C=CC=CC=1>[CH:13]1(/[CH:19]=[C:20](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(Br)cc1F
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1F
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Heat a mixture of 4-bromo-2-fluoro-l -methanesulfonyl-benzene (220 mg, 0.86 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (298 mg, 1.12 mmol), potassium carbonate (356 mg, 2.58 mmol) and tetrakis(triphenylphosphino)palladium(0) (99 mg, 86 μmol) in 40 mL toluene, 5 mL iso-propanol and 5 mL water to reflux for 2 h. After cooling to r.t. extract with ethyl acetate, wash the combined organic extracts with brine, dry them over sodium sulfate, filtrate and concentrate to obtain a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to obtain (E)-3-cyclohexyl-2-(3-fluoro-4-methanesulfonyl-phenyl)-prop-2-en-1-ol (238 mg) as a pale yellow oil. MS (m/e): 295 [(M−H2O)+H].
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[C:15]([I:21])[N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:22]([NH2:25])[CH2:23][CH3:24].CO>C(Cl)Cl>[I:21][C:15]1[N:16]=[C:17]([NH2:20])[C:18]2[N:19]=[C:2]([NH:25][CH2:22][CH2:23][CH3:24])[N:3]([C:13]=2[N:14]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CCCN
Solvent: CO
Solvent: ClCCl
Product: CCCNc1nc2c(N)nc(I)nc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
The reaction was performed with 2-iodo-8-bromoadenosine (5, 90 mg, 0.19 mmol) and propylamine (2.5 ml, 70% w/v in water). Yield 68.8 mg (0.15 mmol, 80%), mp 160–162÷C, Rƒ 0.20 (10% MeOH in CH2Cl2); 1H NMR (DMSO-d6) δ 6.99 (t, 1H, J=4.80 Hz, NH), 6.87 (s, 2H, NH2), 5.80 (d, 1H, J=8.24 Hz, H-1′), 5.67–5.63 (m, 1H, OH-2′), 5.30 (d, 1H, J=6.18 Hz, OH-5′), 5.18 (d, 1H, J=3.77 Hz, OH-3′), 4.56–4.51 (m, 1H, H-2′), 4.09–4.03 (m, 1H, H-3′), 3.96–3.94 (m, 1H, H-4′), 3.62–3.59 (m, 4H, H-5′, NHCH2), 1.57 (q, 2H, J=7.20 Hz, CH2CH3), 0.88 (t, 3H, J=7.50 Hz, CH3); MS m/z 451 (M+H)+; Anal. (C13H19IN6O4) C, H, N.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[SH:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCCBr
Reactant: Sc1cccs1
Product: O=C(O)CCCCCSc1cccs1

Procedure:
Method in which thiophene-2-thiol is reacted with 6-bromo hexanoic acid to obtain 6-(2-thienylsulfanyl)hexanoic acid represented by Chemical Formula [5].
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.I[CH:22]([CH3:24])[CH3:23]>>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH:22]([CH3:24])[CH3:23])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CC(C)I
Product: CCOC(=O)c1c(OC(C)C)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 74 %

Procedure:
Following the procedure of Example 4, this material was prepared in 74% yield from product of Example 2 and 2-iodopropane as a liquid, nD25 1.4210.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[C:6]([C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:16]([Cu])#[N:17]>CN1C(=O)CCC1>[C:16]([C:2]1[C:10]2[C:5](=[C:6]([C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)#[N:17]
Reactant: CCOC(=O)c1cccc2c(Br)c[nH]c12
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c2c(C(=O)O)cccc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
7 g of ethyl 3-bromoindole-7-carboxylate are dissolved in 70 g of NMP, and 4 g of CuCN are added. The mixture is heated to 100-140° C. with stirring. After 3 hours, the mixture is subjected to conventional work-up, giving 3-cyanoindole-7-carboxylic acid.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]1[CH3:30].[H][H]>CO.[Pd]>[O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:7][C@@H:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=2[N:3]1[CH3:30]
Reactant: [H][H]
Reactant: CN1C(=O)C(NC(=O)CCC2CCCCC2)C=C(c2ccccc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)[C@@H](NC(=O)CCC2CCCCC2)C[C@@H](c2ccccc2)c2ccccc21
Yield: 79.6 %

Procedure:
A solution of N-(2,3-Dihydro-2-oxo-1-methyl-5-phenyl-1H-1-benzazepin-3-yl)-3-cyclohexyl-propanamide (250 mg) in methanol (20 ml) was added to a suspension of 10% palladium on carbon (100 mg) in methanol (20 ml). This mixture was subjected to 50 psi of hydrogen on a Parr shaker for two hours. The mixture was then filtered over celite and concentrated at reduced pressure. The resulting foam was crystallized from a mixture of ethyl acetate and hexane, yielding a white solid (200 mg, 80%), which is a cis, racemic mixture. m.p. 156°-158° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[O:48][CH:47]=[C:46]([C:49]([NH2:51])=[O:50])[CH:45]=1>CN(C=O)C.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>[NH3:7].[C:1]([O:5][C:6](=[O:42])[N:7]([C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([C:44]2[O:48][CH:47]=[C:46]([C:49](=[O:50])[NH2:51])[CH:45]=2)=[CH:12][N:13]=1)[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2ncnn12
Reactant: NC(=O)c1coc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(C(N)=O)co2)n2ncnc12
Product: N
Yield: 65.6 %

Procedure:
This compound may be prepared using methods as described for Compound 35, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (137 mg, 0.199 mmol), 5-bromo-furan-3-carboxamide (76 mg, 0.4 mmol) and Pd(PPh3)4 (23 mg, 0.020 mmol) in DMF (1 mL). Purification of the reaction mixture eluting with 98:2 DCM:MeOH and 96:4 DCM:NH3 (7M in MeOH) affords the title compound (33 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:16][C:15]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:13]([CH3:12])[CH:14]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Solvent: C1COCCO1
Product: Cc1cc(C)cc(NS(=O)(=O)c2cccnc2Cl)c1
Yield: 52.1 %

Procedure:
The title compound (791 mg, 2.67 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.09 g, 5.12 mmol) and 3,5-dimethylaniline (709 uL, 5.65 mmol) in 1,4-dioxane (30 mL) using the methods of (IntC1).
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH:29]=[O:30])=[C:21]2[N:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][OH:39])[CH2:33][CH2:32]2)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.O>O1CCCC1>[CH2:4]([O:3][P:1](=[O:2])([O:6][CH2:7][CH3:8])[O:39][CH2:38][CH2:37][N:34]1[CH2:35][CH2:36][N:31]([C:21]2[N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:15][CH:16]=3)[C:28]3[C:23]([C:22]=2[CH:29]=[O:30])=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][CH2:33]1)[CH3:5]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CC(C)(C)c1ccc(-n2c(N3CCN(CCO)CC3)c(C=O)c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOP(=O)(OCC)OCCN1CCN(c2c(C=O)c3ccccc3n2-c2ccc(C(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Diethyl chlorophosphate (0.22 mL, 1.52 mmol) is added to a solution of 1-(4-tert-butylphenyl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]-1H-indole-3-carboxaldehyde (510 mg, 1.26 mmol) and triethylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (5 mL). The resulting orange solution is stirred overnight at room temperature. Water is added and the mixture is extracted with ethyl acetate. The combined ethyl acetate layers are washed with water, with brine, dried and concentrated to give an oil that is purified by chromatography eluting with ethyl acetate and ethyl acetate-5% methanol to afford the phosphoric acid 2-{4-[1-(4-tert-butylphenyl)-3-formyl-1H-indol-2-yl]-piperazin-1-yl}-ethyl ester diethyl ester (280 mg, 68% yield) as a white powder. ESI/MS 542 (M+H)Rt 3.52 min; 1H NMR 10.13 (1H, s); 8.11 (1H, d, J=6 Hz); 7.66 (2H, d, J=6 Hz); 7.46 (2H, d, J=9 Hz); 7.19 (2H, m); 6.92 (1H, d, 9 Hz); 4.04 (6H, m); 3.33 (2H, br s); 3.26 (4H, br s); 2.49 (4H, br s); 1.36 (9H, s); 1.30 (6H, t).
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][OH:10]>>[CH3:9][O:10][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8]
Reactant: CO
Reactant: O=C1CCCCC1Cl
Product: COC1CCCCC1=O
Yield: 90 %

Procedure:
2-methoxycyclohexanone was prepared by dissolving 30 gm. 2-chlorocyclohexanone in 160 ml. methanol and heating the solution in a sealed vessel at 125° C. for approximately four hours. The reactionmass was then cooled and the methanol removed by distillation at reduced pressure. After most of the methanol was distilled off, the residue containing the 2-methoxycyclohexanone was diluted with methylene chloride and extracted with an aqueous solution of sodium hydroxide. After distillation a yield of 90-95% 2-methoxycyclohexanone was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N(C(C)C)CC)(C)C.[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C>[CH:32]1([C:35]([N:37]2[CH2:42][CH2:41][N:40]([C:4]([C:3]3[CH:7]=[C:8]([CH:9]=[CH:10][C:2]=3[F:1])[CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)=[O:6])[CH2:39][CH2:38]2)=[O:36])[CH2:33][CH2:34]1
Reactant: O=C(C1CC1)N1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCN(C(=O)C2CC2)CC1
Temperature: 18 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
2-Fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl)methyl]benzoic acid (D)(15.23 g, 51.07 mmol) was suspended with stirring under nitrogen in acetonitrile (96 ml). Diisopropylethylamine (19.6 ml, 112.3 mmol) was added followed by 1-cyclopropylcarbonylpiperazine (1)(9.45 g, 61.28 mmol) and acetonitrile (1 ml). The reaction mixture was cooled to 18° C. O-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (25.18 g, 66.39 mmol) was added over 30 minutes and the reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was cooled to 3° C. and maintained at this temperature for 1 hour, before being filtered. The filter cake was washed with cold (3° C.) acetonitrile (20 ml) before being dried in vacuo at up to 40° C. to give the title compound as a pale yellow solid (20.21 g).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[N:8][CH:7]=[C:6]2[NH:13][CH2:14][C:15]([NH:17][CH:18]1[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1)=[O:16]>ClCCl.C(O)(C(F)(F)F)=O>[NH:20]1[CH2:19][CH:18]([NH:17][C:15](=[O:16])[CH2:14][NH:13][C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:30])[F:29])[CH:4]=3)[N:9]=[N:8][CH:7]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2cnnc3ccc(C(F)(F)F)cc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(CNc1cnnc2ccc(C(F)(F)F)cc12)NC1CNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(6-(trifluoromethyl)cinnolin-4-ylamino)acetamido)azetidine-1-carboxylate (140 mg, 0.33 mmol,) in dichloromethane (10 ml) and CF3COOH (1 ml). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum to give the title compound as yellow oil.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@@H:14]1O[C@@H](P(OCC)(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.9 %

Procedure:
To a stirring suspension of thymine (551 mg, 3.32 mmol) in dry DMF (3 mL) was added sodium hydride (60% oil dispersion, 133 mg, 3.32 mmol). After stirring the mixture for 30 min at room temperature, a solution of cis-5-bromomethyl-2-diethoxyphosphinoyl-tetrahydrofuran (example 66) (500 mg, 1.66 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 15 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (102 mg, 40%) and then the title compound as an oil (126 mg, 22%).