Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl-].C(C1C=CC(C[P+:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CC=1)(C)C.[PH5].CC(=CCCC(CC=[O:43])C)C>C(O)C>[C:24]1([P:11](=[O:43])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)=CCCC(C)CC=O
Agent: [Cl-]
Agent: [Na]
Agent: [PH5]
Solvent: CCO
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 =1.5172.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.CCOC(C)=O>[CH:20]1([CH2:19][O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)[CH2:22][CH2:21]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
A solution of N-boc-4-piperidinemethanol (0.500 g, 2.322 mmol) in DMF (10 mL) was added drop wise to a suspension of sodium hydride (60% in mineral oil) (0.186 g, 4.645 mmol) in dry DMF (15 mL) at 0 C. The mixture was stirred at 0 C for 15 minutes and room temperature for 10 minutes before being cooled down again and (bromomethyl)cyclopropane (0.227 mL, 2.322 mmol) was added drop wise. The reaction mixture was stirred at 0 C for 10 minutes, room temperature for 1 h and 80 C for 4 h. The reaction mixture was diluted with EtOAc (60 mL) and washed with water (3×20 mL). The aqueous washes were combined and re-extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated to provide the title compound as a colorless oil (0.614 g, 98%). Method B HPLC-MS: MH+ requires m/z=270 Found: m/z=214 (MH+-tBu), Rt=2.33 min (83%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30](O)=[O:31])=[CH:5][CH:4]=1)#[N:2].[CH3:33][CH2:34][N:35](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>CN(C=O)C>[CH2:34]([NH:35][C:30]([C:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:14]2[C:15](=[O:18])[NH:16][N:17]=[C:13]2[N:12]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:11]=1[CH3:29])=[O:31])[CH3:33]
Reactant: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2n[nH]c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 49.2 %

Procedure:
To a solution of Example 9 (100 mg, 0.23 mmol) in DMF (3 ml), were added DIPEA (102 μL, 0.6 mmol) and HATU (133 mg, 0.35 mmol) and the reaction mixture was stirred at RT for 45 mins. Ethylamine (2 M in THF, 175 μL, 0.35 mmol) was then added, and stirring at RT was continued for 16 hours. Further ethylamine (2 M in THF, 175 μL, 0.35 mmol) was added, the temperature was raised to 60° C., and stirring was continued for 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 80-100% EtOAc in cyclohexane to yield the title compound as a white solid (53 mg).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:11]1[C:16]([CH:17]([CH:20]=O)[CH:18]=O)=[CH:15][CH:14]=[C:13]([Cl:22])[CH:12]=1>N1C=CC=CC=1>[Cl:22][C:13]1[CH:14]=[CH:15][C:16]([C:17]2[CH:18]=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][CH:20]=2)=[CH:11][CH:12]=1
Reactant: O=CC(C=O)c1ccc(Cl)cc1
Reactant: N=C(N)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: Clc1ccc(-c2cnc(-c3ccncc3)nc2)cc1
Yield: 55.9 %

Procedure:
Isonicotinamidine, hydrochloride (0.488 g) and 2-(4-chlorophenyl)malondialdehyde (0.566 g) were combined in anhydrous pyridine (10 ml) and heated to reflux under nitrogen, for 18 h. The resultant dark solution was cooled and poured onto ice-water (150 ml) and the mixture extracted with ethyl acetate (150 ml, then 50 ml). The combined organic extracts were washed with water (3×10 ml), saturated brine (20 ml), dried (Na2SO4), evaporated to dryness under reduced pressure and the residue purified by silica gel column chromatography with 3.5% methanol/dichloromethane as eluent, to give the title compound as a white solid (0.463 g, 56%).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[O:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CC#N>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:27]3[CH2:28][CH2:29][CH2:30][O:26]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CNOC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCCO3)ccc2n1CC1CCOCC1
Yield: 34.6 %

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (61 mg, 0.17 mmol), isoxazolidine hydrochloride (44 mg, 0.40 mmol), DIPEA (0.2 mL, 149 mg, 1.15 mmol) and DMAP (50 mg, 0.41 mmol) in MeCN (5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:1) on silica gel to give 24 mg (36%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.61 (m, 4 H), 1.63 (s, 9 H), 2.02-2.19 (m, 2 H), 2.25-2.42 (m, 1 H), 3.29-3.38 (m, 2 H), 3.64-3.73 (m, 2 H), 3.86 (t, J=7.13 Hz, 2 H), 3.88-3.96 (m, 2 H), 4.49 (d, J=7.42 Hz, 2 H), 7.98 (d, J=1.56 Hz, 1 H), 7.99 (s, 1 H), 8.24 (d, J=0.78 Hz, 1 H); MS (ESI) (M+H)+=408.0; Anal. Calcd for C20H29N3O4S+1.20 TFA+0.20 EtOAc (561.99): C, 49.58; H, 5.70; N, 7.48. Found: C, 49.74; H, 5.53; N, 7.46.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C.C(OC(=O)C)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[N+:27]([O-:29])=[O:28])[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=O)Nc1ccc2cccc([N+](=O)[O-])c2c1NC(=O)C(=O)OCC
Temperature: 0 °C

Procedure:
A partial suspension of 1,2-diethoxalylaminonaphthalene (1,79 g, 5 mmol) in 7 ml of acetic acid and 7 ml of acetic anhydride was treated dropwise with a solution of nitric acid (1.8 ml, 43 mmol, d 1.52) in 7 ml of acetic acid, with stirring at 0° C. The resulting solution was stirred at 0° C. for 11/2 h and then poured on 150 ml of ice/water. The yellow precipitate was isolated, dried and recrystallized from ethanol with decolourising carbon giving 0.67 g (33%) of the required compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([OH:21])=O)[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:22][N:23](C)C=O.S(Cl)(Cl)=O.CN>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:18][C:19]([NH:23][CH3:22])=[O:21])[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nc3ccc(Cl)nc3n2CC(=O)O)cc1
Reactant: CN(C)C=O
Agent: CN
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(C)cc2)nc2ccc(Cl)nc21
Temperature: 25 °C
Yield: 63.5 %

Procedure:
A slurry of 5-chloro-2-(4-methylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (2.8 g, 0.0093 mole) in tetrahydrofuran (11.3 ml) and dimethylformamide (0.68 g, 0.0093 mole) was cooled in an ice bath under nitrogen. Thionyl chloride (1.22 g, 0.0102 mole) was added dropwise to the stirred suspension. After stirring at room temperature for twenty minutes, the solution was cooled again in an ice bath and a solution of methylamine in tetrahydrofuran (21.5 ml of a 2.59M solution, 0.056 mole) was added dropwise. The suspension was stirred at room temperature under nitrogen for one hour and then the solvents were removed under reduced pressure. The residue was triturated in water (100 ml) and the resulting solid was collected by filtration and rinsed three times with water. The solid was dissolved in hot isopropyl alcohol, filtered while hot, and brought to the cloud point with isopropyl ether. Upon cooling, a solid precipitated which was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 70° C. to give 1.86 g (64% yield) of title compound, mp>250° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O-:20])=[O:19])[C:13]([O:15]CC)=[O:14].NC(N)=[S:23].[OH-].[Na+].Cl>C(O)C>[SH:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([OH:20])=[O:19])[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(CCCCCCCCCCBr)C(=O)[O-]
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(CCCCCCCCCCS)C(=O)O

Procedure:
Reflux a solution of ethyl 2-(10-bromo-decyl)malonate (5.5 mmole) and thiourea (6.6 mmole) in 95% ethanol (25 mL) for 5 hours and then add an aqueous NaOH (2.0 M, 25 mL) and reflux for another 15 hours. Then, add an aqueous HCl (2.0 M) until the solution becomes acidic (approximately pH ˜2). Extract the reaction mixture with ether three times and wash and dry the combined organic layers with saturated NaCl solution with MgSO4. The product, 2-(10-mercaptodecyl)-propanedioic acid, can then be obtained by removal of solvent under reduced pressure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]([O:22][CH3:23])[N:9]([C:12]3[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=3)[C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[C:31]([O:32][CH3:33])=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1.C([O-])([O-])=O.[Na+].[Na+].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.O>[CH3:33][O:32][C:31]1[CH:30]=[C:29]([C:2]2[N:7]=[C:6]3[CH:8]([O:22][CH3:23])[N:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH:16]=4)[C:10](=[O:11])[C:5]3=[CH:4][CH:3]=2)[CH:28]=[N:27][C:26]=1[O:25][CH3:24]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Reactant: COC1c2nc(Cl)ccc2C(=O)N1c1cnn(CC(F)(F)F)c1
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: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc3c(n2)C(OC)N(c2cnn(CC(F)(F)F)c2)C3=O)cnc1OC
Temperature: 110 °C
Reaction time: 0.67 h

Procedure:
As shown in step 17-v of Scheme 17, to Compound 2058 (293 mg, 0.85 mmol), 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (269 mg, 1.01 mmol), Na2CO3 (179 mg, 1.69 mmol), and Pd(PPh3)4 (98 mg, 0.085 mmol) was added DMF (10 mL), followed by the addition of water (2 mL). The reaction vessel was evacuated, placed under an atmosphere of nitrogen, then warmed to 110° C. (sand bath). After 16 hours the reaction mixture was partitioned between EtOAc and water (100 mL each). The organics were washed with water (70 mL), brine (70 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was dissolved/suspended in EtOAc (7 mL) and heated with swirling in a water bath at 50° C. for 40 minutes. The resulting mixture was treated with hexanes (5 mL) and swirled an additional 5 minutes at 50° C. After cooling to 23° C., the resulting solid was collected by filtration and washed with 1:1 (EtOAc:hexanes, 5 mL) to give 2-(5,6-dimethoxypyridin-3-yl)-7-methoxy-6-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Compound 256) as a mixture of enantiomers: ESMS (M+H) 450.44; 1H NMR (CDCl3, 300 MHz) δ 8.57 (d, J=3 Hz, 1H), 8.35 (s, 1H), 8.27 (s, 2H), 7.99 (d, J=3 Hz, 1H), 7.93 (s, 1H), 6.40 (s, 1H), 5.22 (q, J=9 Hz, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 3.13 (s, 3H).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([CH:25]=O)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].C(C1C=CC(C2SC=CC=2)=CN=1)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:9]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:24][C:23]([C@H:25]3[O:8][CH2:7][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][O:6]3)=[CH:22][CH:21]=2)=[CH:16][N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCc1ccc(-c2ccc(C=O)s2)cn1
Reactant: CCCC(CO)CO
Agent: CCCCCc1ccc(-c2cccs2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCc1ccc(-c2ccc([C@H]3OC[C@H](CCC)CO3)s2)cn1
Reaction time: 3 h

Procedure:
A mixture of 1.2 g of 2-propylpropane-1,3-diol, 2.59 g of 5-(2-pentyl-5-pyridyl)-2-formyl-thiophene (obtainable by formylation of 5-(2-pentyl-5-pyridyl)-thiophene via a Vilsmeier reaction), 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled for 3 hours, using a water separator, cooled, washed with water and evaporated. 5-(2-Pentyl-5-pyridyl)-2-(trans-5-propyl-1,3-dioxan-2-yl)-thiophene is obtained.
Reaction SMILES: [Si](OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)N=1)=O)(C(C)(C)C)(C)C.[CH2:46]([O:53][C:54]1[C:55]([C:74]([OH:76])=O)=[N:56][C:57]([CH2:61][C:62]2([C:67]3[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=3)[CH2:66][CH2:65][CH2:64][CH2:63]2)=[N:58][C:59]=1[OH:60])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[CH2:77]([NH:84][CH2:85][CH2:86][O:87][Si:88]([C:91]([CH3:94])([CH3:93])[CH3:92])([CH3:90])[CH3:89])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[CH2:77]([N:84]([CH2:85][CH2:86][O:87][Si:88]([C:91]([CH3:94])([CH3:93])[CH3:92])([CH3:89])[CH3:90])[C:74]([C:55]1[C:54]([O:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[C:59]([OH:60])[N:58]=[C:57]([CH2:61][C:62]2([C:67]3[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=3)[CH2:63][CH2:64][CH2:65][CH2:66]2)[N:56]=1)=[O:76])[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
This compound was prepared by following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) and benzyl-[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-amine (8I).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:19]([O-:24])([O:22][CH3:23])[O:20][CH3:21]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:11]=[CH:12][C:13]([CH:16]([P:19]([O:22][CH3:23])([O:20][CH3:21])=[O:24])[OH:17])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COP(=O)(OC)C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 4-formyl-benzoic acid benzyl ester (0.50 g, 2.08 mmol) in THF (2.0 mL) was cooled to 0° C., then dimethyl phosphite (0.25 g, 2.29 mmol) and N,N,N′M′-tetramethyl-guanidine (0.02 g, 0.21 mmol) was added dropwise. The reaction mixture was warmed to ambient temperature. After stirring for 45 mins the reaction mixture was diluted with EtOAc and washed with 1N aqueous HCl (2×), brine, then dried (MgSO4) and concentrated in vacuo to give the title compound: MS: cal'd 351 (MH+), exp 351 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[CH:3]=1.C(O)(=O)C.[N:19]([O-])=[O:20].[Na+]>O>[NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[O:13])[NH:5][C:4](=[O:14])[C:3]=1[N:19]=[O:20]
Reactant: O=N[O-]
Reactant: CCCCCn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=O
Reaction time: 2 h

Procedure:
To a stirring mixture of 6-amino-1-pentylpyrimidine-2,4(1H,3H)-dione (4.0 g, 0.020 mol) and acetic acid (20 mL, 0.4 mol) in water (20 mL) was slowly added sodium nitrite (1.5 g, 0.022 mol). Stirring was continued at room temperature for 2 h at which time the reaction mixture became pink and precipitate formed. The reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in aqueous NaOH solution and extracted with methylene chloride to remove byproducts. The aqueous solution was neutralized with HCl and concentrated. The residue was treated with methanol and filtered. The filtrate was concentrated to give the desired product as pink solid. LCMS calculated for C9H15N4O3 (M+H): 227.1. found: 227.1 (M+H), 249.1 (M+Na).
Reaction SMILES: [N:1]1[C:10]2[N:9]=[CH:8][CH:7]=[C:6](O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ncccc12
Product: Clc1nccc2ncccc12
Temperature: 80 °C
Yield: 87 %

Procedure:
The product from Example 228d (0.250 g, 1.71 mmol) was combined with phosphorous oxychloride (4 mL) and heated under a nitrogen atmosphere at 80° C. for 18.5 h followed by vacuum distillation to remove the volatiles. The residue was slurried with ice and made basic (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, water washed and dried under vacuum to give a gray solid (0.245 g, 87%) sufficiently pure for use as isolated.
Reaction SMILES: C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[NH2:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19].[CH2:24]([O:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([CH2:24][O:31][C:32]([NH:16][C@@H:17]([CH2:21][C:22]#[N:23])[C:18]([OH:20])=[O:19])=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N#CC[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CC#N
Product: N#CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
Bis (trimethylsilyl)trifluoroacetamide (9.4 mL, 35 mmol.) was added to a suspension of (αS)-amino-3-cyanopropanoic acid (2.0 g., 17.5 mmol.) in 10 mL of dry acetonitrile and the reaction mixture was stirred for 3 hours. Benzylchloroformate (2.5 mL, 17.5 mmol) was added, the reaction mixture was stirred overnight, concentrated in vacuo, and dissolved in ethyl acetate (200 mL). The organic solution was washed with water (2×) and brine, dried (Na2SO4), and concentrated in vacuo. Crystallization from isopropyl ether yielded 3.82 g. of the title A product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]#[N:9].[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][N:11]1[C:8]([NH2:9])=[C:3]2[C:2]([CH2:7][CH2:6][CH2:5][CH2:4]2)=[N:12]1
Reactant: CNN
Reactant: N#CC1CCCCC1=O
Solvent: CCO
Product: Cn1nc2c(c1N)CCCC2

Procedure:
A solution of 2-oxocyclohexanecarbonitrile 16 (10 g, 81.2 mmol) and methyl hydrazine 15 (3 equiv, 11.2 g) in 150 mL of absolute ethanol was refluxed for 20 hrs and was concentrated on rotavapor to dryness. The crude product was recrystallized from methanol to afford the desired product 17. (Reference for the preparation of compound 17: J. Am. Chem. Soc. 1959, 81, 2448-2452)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[CH:5]=[CH:4][C:3]=1[C:9](=[O:12])[CH2:10][CH3:11]
Reactant: O=C([O-])[O-]
Reactant: CCC(=O)c1ccc(O)cc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCC(=O)c1ccc(OC)cc1O
Yield: 86.7 %

Procedure:
6.00 g of 2′,4′-dihydroxypropiophenone was dissolved in 70 ml of acetone. Thereafter, 7.09 g of potassium carbonate and 3.03 ml of methyl iodide were successively added to the reaction solution. The reaction solution was then heated to reflux. Approximately 3 hours later, the reaction solution was stood to cool and then filtered. The filtrate was concentrated under a reduced pressure. A saturated sodium chloride solution and ethyl acetate were added to the residue, so as to separate an organic layer. The obtained organic layer was washed with 2 N hydrochloric acid and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was solidified from hexane-ethyl acetate, so as to obtain 5.64 g of the subject compound. 1H-NMR (CDCl3) δ (ppm): 1.23 (t, J=7.2 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 6.40-6.45 (m, 2H), 7.65 (dd, J=1.6 Hz, 8.0 Hz, 1H), 12.8 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:15])([CH3:14])[CH2:12][OH:13])[NH:8]2)=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[CH3:19][C:20]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1>C(Cl)Cl>[Si:23]([O:13][CH2:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([N+:16]([O-:18])=[O:17])=[C:2]([F:1])[CH:10]=2)([CH3:15])[CH3:14])([C:20]([CH3:22])([CH3:21])[CH3:19])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a stirred solution of 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (10.0 g) in CH2Cl2 was added TBSCl (8.9 g), imidazole (8.1 g, 0.12 mol) at room temperature. The mixture was stirred overnight. The solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-6-fluoro-5-nitro-1H-indole (5.3 g, 38%). 1H NMR (300 MHz, CDCl3) 9.51 (s, 1H), 8.31 (d, J=7.5 Hz, 1H), 7.02 (d, J=11.7 Hz, 1H), 6.32 (s, 1H), 3.63 (s, 2H), 1.35 (s, 6H), 0.99 (s, 9H), 0.11 (s, 6H).