Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH2:27][CH3:28])[N:25]=[CH:24][CH:23]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([N:26]1[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:30]3[CH:35]=[CH:34][N:33]=[CH:32][N:31]=3)(=[O:9])=[O:8])=[C:11]([F:29])[CH:12]=2)=[CH:23][CH:24]=[N:25]1)[CH3:28]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 51.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.45 g, 0.78 mmol) prepared in Example 115a, triethylsilane (0.62 mL), trifluoroacetic acid (0.78 mL) and dichloromethane (7.8 mL), to yield the title compound (173 mg, 52%) as a colorless solid.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[CH:11][C:12]3[C:13]([CH:19]([CH3:21])[CH3:20])=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([C:11]1[C:12]2[C:13]([CH:19]([CH3:20])[CH3:21])=[CH:14][C:15]([F:18])=[CH:16][C:17]=2[N:9]2[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=12)=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCC1C(C)C(=O)[O-]
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc(Cl)c(Cl)c1)c1n2CCC1CC(=O)O

Procedure:
Starting from methyl(6-fluoro-8-isopropyl-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 44, Step 2) and 3,4-dichlorobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[OH:8])[CH2:2][CH2:3][CH3:4].[C:11]([CH2:13][C:14](O)=[O:15])#[N:12].CN(C=O)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:5][C:6]([CH:7]([O:8][C:14](=[O:15])[CH2:13][C:11]#[N:12])[CH3:9])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C(C)O
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCOC(=O)C(C)OC(=O)CC#N

Procedure:
A mixture of 292.32 g of butyllactate, 204.14 g of cyanoacetic acid, and 14.66 g of 4-dimethylaminopyridine (DMAP) in 2000 ml of CH2Cl2 was stirred in a 3 L three-neck round bottom flask equipped with a mechanical stirrer. About 50 ml of N-N′-dimethylformide (DMF) was added to make a clear solution. The above clear solution was chilled in an ice water bath. A separately prepared dicyclohexylcarbodiimide (DCC) solution (495.19 g in 500 ml CH2Cl2) was added to the above chilled solution by using an addition funnel. White precipitate formed within five minutes after the start of the addition. The reaction mixture was left stirred overnight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[CH2:18](I)[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[N:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:18][CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
3-Bromo-N-tert-butoxycarbonylaniline (0.82 g, 3.0 mmol) was dissolved in anhydrous DMF (15 ml) and cooled to 0° C. Sodium hydride (0.145 g, 3.6 mmol, 1.2 eq.) was added to the solution. The reaction stirred at 0° C. for 10 minutes then was warmed to room temperature. After 30 minutes at room temperature the reaction was cooled to 0° C. and Ethyl iodide (0.27 ml, 3.3 mmol, 1.1 eq.) was added over ˜1 minute. The reaction was stirred at 0° C. for 5 minutes then was warmed to room temperature. The reaction stirred at room temperature for 22 hours and was then cooled to 0° C. and quenched with a saturated bicarbonate solution and extracted with EtOAc (2 times). The combined organic layers were washed with H2O (5 times) then brine. The organic phase was dried with MgSO4/Na2SO4, filtered and the solvent was removed in vacuo to give 0.93 g of crude product which was used as is. HPLC ret time 11.83 min. (100%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH:9]([NH:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]2[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24](OCCOC)[CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:24]2[CH:23]=[C:22]([NH:21][C@@H:18]3[CH2:19][CH2:20][C@H:15]([C:13]([NH:12][CH:9]([CH3:11])[CH3:10])=[O:14])[CH2:16][CH2:17]3)[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCn1cncn1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCn3cncn3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide was prepared in 2 steps from 2-(1H-1,2,4-triazol-1-yl)ethanol using a procedure analogous to that used to prepare cis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (104 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)[C:5](OCC)=[O:6])#[N:2]>C(O)(=O)C.O=[Pt]=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:3][CH2:1][NH:2][C:5]2=[O:6])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(CC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C1NCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of the product from Example 58A (20 mg, 0.063 mmol) in acetic acid (4 mL) was added to PtO2 (4.00 mg, 0.018 mmol) in a 50 mL pressure bottle and stirred at room temperature for 12 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 274 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH2:8][CH2:7][C@@H:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:5]1.[CH:25]1([CH2:28]Br)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([CH2:28][N:5]2[C@H:6]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:7][CH2:8][CH2:9][C@H:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:4]2=[O:3])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](c2ccccc2)NC1=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 85.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 20.6 mg, 0.52 mmol) was added to a solution of tert-butyl (3S,7S)-2-oxo-7-phenylazepan-3-ylcarbamate (143 mg, 0.47 mmol) and cyclopropylmethyl bromide (0.11 mL, 1.18 mmol) in N,N-dimethylformamide (1 mL) at 0 □C, and the mixture was allowed to warm to ambient temperature. After 14 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (10% ethyl acetate/hexanes→30% ethyl acetate/hexanes) gave the title compound (144 mg). MS 359 (M+1).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>S(=O)(=O)(O)O>[C:6]1([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][C:17]([N+:1]([O-:4])=[O:2])=[CH:16][CH:15]=3)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CCCc1c(-c2ccccc2)[nH]c2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCc1c(-c2ccccc2)[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 5 °C
Yield: 30 %

Procedure:
A solution of 1.19 g (4.10−3 mol) of sodium nitrate in 50 ml of concentrated sulfuric acid is added at 0-5° C., with stirring, to a solution of 3.67 g (13.15.10−2 mol) of 2-pheny-1H-indole-3-butanoic acid in 200 ml of concentrated sulfuric acid. Stirring is maintained at 5° C. for 20 min and the reaction medium is then poured into a mixture of water and ice. The yellow precipitate formed is filtered off and washed on the filter with water and with a small amount of petroleum ether. The product is then dried under reduced pressure and purified by chromatography on silica gel using a hexane/ethyl acetate mixture (1/1) as the eluent to give 1.3 g of the expected product in the form of a yellow solid with a yield of 30%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35](Cl)(=[O:37])=[O:36])([O:28][CH3:29])=[O:27]>>[CH3:29][O:28][C:26]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[S:35]([N:23]1[CH2:22][CH2:21][CH:20]([NH:19][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=3[O:17][CH3:18])=[CH:6][N:5]=2)[CH2:25][CH2:24]1)(=[O:37])=[O:36])=[O:27]
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: COC(=O)c1sccc1S(=O)(=O)Cl
Product: COC(=O)c1sccc1S(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
This compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone, Example 59, and 2-carbomethoxy-3-thiophenesulfonyl chloride (Maybridge) by the procedure described in Example 152. HR-MS (ES, m/z) calculated for C23H25FN5O6S2 [(M+H)+] 550.1225, observed 550.1232.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=O.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][NH:23][CH2:22][CH2:21]2.C(O)(=O)C.ClC(Cl)C.C([BH3-])#N>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH2:24][N:23]([CH2:1][C:3]1[CH:4]=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[O:13])[N:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)[CH2:22][CH2:21]2
Reactant: Clc1ccc2c(c1)CCNC2
Reactant: O=Cc1cc(C(=O)O)c(=O)n2ccccc12
Agent: [BH3-]C#N
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)c1cc(CN2CCc3cc(Cl)ccc3C2)c2ccccn2c1=O
Temperature: 120 °C

Procedure:
In a 2-5 mL Emrys™ process vial, a mixture of the 1-formyl-4-oxo-4H-quinolizine-3-carboxylic acid (76 mg, 0.35 mmol), 6-chloro-1,2,3,4-tetrahydroisoquinoline (82 mg, 0.49 mmol), glacial acetic acid (0.12 mL, 2.1 mmol) and 1.8 mL of dichloroethane was stirred vigorously. To the stirring mixture was added resin-bound MP-cyanoborohydride (343 mg, 0.70 mmol). The mixture was heated via Emrys Optimizer™ microwave to 120° C. for 30 minutes. Filtration and solvent removal provided material, which was subjected to preparative reverse phase HPLC. Collection of product containing fractions and removal of solvent yielded the title compound that gave a proton NMR spectrum consistent with theory and a high resolution mass spectrum (ES+) m/z of 369.1011 calculated for M+H+ [C20H17Cl1N2O3: 369.1001]: 1H NMR (500 MHz, CD3OD) δ 9.59 (d, J=7.1 Hz, 1H), 8.74 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.18 (t, J=73 Hz, 1H), 7.73 (t, J=6.6 Hz, 1H), 7.32 (s, 1H), 7.27 (d, J=8.3 Hz, 1H), 7.14 (d, J=8.6 Hz, 1H), 4.87 (s, 2H), 4.47 (s, 2H), 3.69 (bs, 2H), 3.20 (t, J=6.0 Hz, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(-c2ccn(Cc3ccc(C(F)(F)F)cc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and bromomethyl-4-trifluoromethyl-benzene as described in Example 49 and isolated as yellow solid (0.075 g, 50% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 2H), 7.70 (d, J=4 Hz, 1H), 7.61 (d, J=8 Hz, 2H), 7.44 (d, J=4 Hz, 1H), 7.26-7.36 (m, 3H), 6.88 (d, J=2 Hz, 1H), 6.13 (t, J=5 Hz, 1H), 5.41 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=458.1; Rt=1.35 min; HRMS (M+H)+=458.13.
Reaction SMILES: [C:1]1([C:6]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]([OH:15])=O)=O)[S:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:17][NH2:18]>C(O)C>[S:5]1[CH:4]=[CH:3][CH:2]=[C:1]1[C:6]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13](=[O:15])[NH:18][N:17]=1
Reactant: NN
Reactant: O=C(O)c1ccsc1C(=O)c1cccs1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccs2)c2sccc12
Yield: 88.6 %

Procedure:
0.70 g of 2-(2-thenoyl)-3-thiophene carboxylic acid and 0.22 g of hydrazine hydrate were dissolved in 20 ml of ethanol, and the solution was refluxed for 5 hours. After cooling the solution, it was crystallized by adding ether, thereby obtaining 0.61 g of 7-(2-thienyl)thieno[2,3-d]-pyridazine-4(5H)-one.
Reaction SMILES: [C:1]1([P:7]([CH2:14][P:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1CCCCC1>[CH:16]1([P:15]([CH2:14][P:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: c1ccc(P(CP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Reactant: [H][H]
Solvent: C1CCCCC1
Product: C1CCC(P(CP(C2CCCCC2)C2CCCCC2)C2CCCCC2)CC1
Temperature: 100 °C

Procedure:
A 300 ml. stainless steel high pressure reactor was charged, under a nitrogen atmosphere at atmospheric temperature, with a solution of ##STR1## hereinafter referred to as Nb(OC6H3Ph2 --2,6)2 (CH2C6H4 --4Me)3 (2.2 g., 2.5 mmol.) and bis(di-phenylphosphino)methane (25.0 g., 65.1 mmol.) in cyclohexane (55 ml.). The reactor was pressurized with hydrogen (1,200 psi) and heated at 100° C. for four days. During the course of the reaction the pressure dropped requiring the repressurization of the reactor four times. Thereupon, the reactor was cooled and the hydrogen gas vented. The cyclohexane was removed in vacuo and water (30 ml.) was added to the mixture. The mixture was extracted with diethyl ether (200 ml.) which extraction was repeated four times to yield a clear colorless solution. The ether was removed and the resultant solution was recrystallized from hot ethanol (120 ml.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[I:22]Cl>CO>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([I:22])=[C:11]([CH:10]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClI
Reactant: OCc1cccc(OCc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OCc1cc(OCc2ccccc2)ccc1I
Reaction time: 1 h
Yield: 71 %

Procedure:
To a well stirred solution of 3-benzyloxybenzyl alcohol (5.5 g, 25.7 mmol) in methanol (100 mL) and sodium hydrogencarbonate (8.4 g, 100 mmol) was added a 1.0 M solution of iodine monochloride in dichloromathane (30 mL) at 0° C. The reaction mixture was brought to room temperature and stirring continued for additional 1 h. The reaction mixture was concentrated and then diluted with dicholomethane (150 mL), washed with 10% aqueous sodium thiosulfate and dried (Na2SO4). The desired compound was purified by flash chromatography (silica) using 20% ethyl acetate in hexane to give 5-benzyloxy-2-iodobenzyl alcohol (6.2 g, 71% yield). The alcohol (4.2 g, 12.4 mmol) was dissolved in dichloromethane (100 mL) added acetic anhydride (2.52 g, 24.7 mmol) and catalytic amount of 4-dimethylaminopyridine. The reaction mixture was then stirred for 12 h, washed with aqueous sodium hydrogencarbonate and then dried (Na2SO4) to give acetic acid 5-benzyloxy-2-iodo-benzyl ester in quantitative yield. MS (ESI) 405 (M+Na); Rf=2.27.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CCOCC>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C1=COCCC1
Reactant: C=CCCCCO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8.5 g 5-hexen-1-ol in 100 mL tetrahydrofuran is added 14 mL dihydropyran followed by 0.5 g p-toluenesulfonyl chloride. The mixture is stirred at room temperature for 18 hours and then diluted with ether. The mixture is then washed with saturated aqueous sodium bicarbonate, dried, filtered and evaporated. The resulting oil is chromatographed over silica gel using hexane/ether (18:1) as eluent to give 6-(2-tetrahydropyranyloxy)-hex-1-ene; NMR (CDCl3): delta 5.85 (m,1H), 4.6 (brs,1H).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(O)c(Br)n1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C)nc1Br
Yield: 88.3 %

Procedure:
A stirred mixture of 2-bromo-3-hydroxy-6-methyl-pyridine (7.89 g, 42.0 mmol), potassium carbonate (11.60 g, 83.9 mmol) and iodomethane (8.93 g, 62.9 mmol, 3.92 mL) in acetone (100 mL) was heated under reflux overnight. The mixture was filtered, evaporated and purified on silica gel (hexane:ethyl acetate, 95:5 to 9:1) to give the desired product as a white solid (7.49 g, 88.3%). 1H NMR (500 MHz, CDCl3): δ2.46 (s, 3H), 3.87 (s, 3H), 7.04 (s, 2H).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[P:8]([Cl:11])(Cl)Cl>C1C=CC=CC=1>[CH:1]([N:4]([P:8]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])[Cl:11])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: ClP(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: c1ccccc1
Product: CC(C)N(C(C)C)P(Cl)N(C(C)C)C(C)C

Procedure:
The synthesis shown in FIG. 2A can be carried out, for example, by adding anhydrous N,N-diisopropylamine to a solution of phosphorus trichloride in dry benzene to produce bis(N,N-diisopropylamino)chlorophosphine, and reacting it in situ with 2-(N-formyl-N-methyl) aminoethan-1-ol to produce phosphordiamidite 120 in about 73% yield. Phosphordiamidite 120 can then be reacted with a suitably protected nucleophile, such as 5′-O-(4,4′-dimethoxytrityl)-2′-deoxythymidine (Barone et al., Nucl. Acids Res., 12, 4051-4061 (1984)) to produce deoxyribonucleoside phosphoramidite 101 (FIG. 2A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:9])[CH:5]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Reactant: Clc1cc(Cl)cc(I)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(Cl)cc(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,3-dichloro-5-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.92 (s, 3H), 4.95 (s, 2H), 6.47 (d, 1H), 6.65-6.78 (m, 2H), 7.13 (t, 2H), 7.33-7.43 (m, 8H), 7.52 (d, 1H), 7.93 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[OH:19].[O:20]1[CH2:25][CH2:24][N:23]([CH:26](Cl)[CH3:27])[CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:5]2[O:19][CH2:27][CH2:26][N:23]1[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1ccc2oc(=O)c(-c3ccccc3)c(O)c2c1
Reactant: CC(Cl)N1CCOCC1
Product: Cc1ccc2oc(=O)c(-c3ccccc3)c(OCCN3CCOCC3)c2c1
Yield: 77 %

Procedure:
This compound is prepared as described in Example 8 from 19.4 g. (0.077 mol) of 6-methyl-4-hydroxy-3-phenyl-coumarin and 16.1 g. (0.1 mol) of 2-morpholino-2-chlorethane. Weight 21.7 g.; yield 77% (theoretical yield 28.2 g.). M.P. 96° C.
Reaction SMILES: [CH:1]1([N:6]([C:13]2[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=2)[CH2:7][CH2:8][C:9](OC)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+].[Cl-]>[Fe].CCO.O>[Cl:22][C:15]1[N:16]=[CH:17][C:18]2[NH:19][C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[N:14]=1
Reactant: COC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Yield: 43.7 %

Procedure:
Methyl 3-[cyclopentyl(2-chloro-5-nitropyrimidin-4-yl)amino]propanoate (1.00 g, 0.003 mol) and NH4Cl (1.38 g, 0.025 mol, 8.5 eq) were added to EtOH/H2O (4:1 ml, 10 ml) and the mixture heated to reflux before the portion-wise addition of iron powder (1.36 g, 0.024 mol, 8 eq). The RM was then refluxed for an additional 2 h. Progress of the reaction was monitored by HPLC and when no SM remained the RM was filtered hot through celite. The celite was washed with EtOAc (10 ml) and EtOH (10 ml) [both hot] and the filtrate evaporated under reduced pressure and further dried in vacuo to give the product as a brown solid (350 mg, 43%); Rt=12 min (Vydac 1); MS+ve: 267.2.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Reactant: CN1CCNCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 68 %

Procedure:
To a suspension of 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (1.53 g, 10 mmol) in DMF (20 mL) was added 1-methylpiperazine (1.2 g, 12 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (EDAC, 2.3 g, 12 mmol), 1-hydroxybenzotriazole (HOBt, 1.6g, 12 mmol) and triethylamine (3.2 mL, 24 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction was concentrated, diluted with water and extracted with ethyl acetate (5×). The combined ethyl acetate was concentrated to a volume of 20 mL and triturated with hexane (10 mL). The resulting solid was collected by vacuum filtration to give 1.6 g (68%) of 3-methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H, NH), 9.7 (s, 1H, CHO), 6.35 (s, 1H), 3.58 (m, 4H 2×CH2), 2.30 (m, 7H, 2×CH2 & CH3), 2.18 (s, 3H, CH3). MS 236 [M++1].